ALBERT

Beschreibung: The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review much recent literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD + and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age-related pathologies, which are caused by or exacerbated by senescent cells in vivo. Replicative cellular lifespan is regulated by myriad cellular factors and processes, including telomeres, oxygen, DNA damage signaling, growth factors and metabolism. In this review, we will explain some of the molecular means by which these and other factors mediate cellular lifespan.

Beschreibung: Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations ( healthy young UK men and Scandinavian diabetic patients ) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold ( P  〈 0·01) whilst increasing ACE expression within a physiological range (〈1·8-fold at 48 h; P  〈 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems, which also regulate diverse aspects of whole-body metabolism and mitochondrial function. We demonstrate that ACE expression appears to be regulated by mitochondrial UCPs.

Beschreibung: Positive transcription elongation factor (P-TEFb) plays an important role in host cell and viral gene expression. Many viruses, including Herpes Simplex Virus 1, have evolved strategies to hijack this key factor via their own regulatory proteins. The central role of P-TEFb in viral life cycles raises the possibility that Cdk9 inhibitors might be useful antiviral agents. See article “P-TEFb goes viral” by Justyna Zaborowska, Nur F. Isa and Shona Murphy in this issue.

Beschreibung: Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and is a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior. Tumors are a mixture of differentially evolved subpopulations of cells in constant evolution. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and is a potential contributor to the cancer stem cell phenotype and its enhanced tumorigenicity.

Beschreibung: Eukaryotic gene expression is extensively controlled at the level of mRNA stability and the mechanisms underlying this regulation are markedly different from their archaeal and bacterial counterparts. We propose that two such mechanisms, nonsense-mediated decay (NMD) and motif-specific transcript destabilization by CCCH-type zinc finger RNA-binding proteins, originated as a part of cellular defense against RNA pathogens. These branches of the mRNA turnover pathway might have been used by primeval eukaryotes alongside RNA interference to distinguish their own messages from those of RNA viruses and retrotransposable elements. We further hypothesize that the subsequent advent of “professional” innate and adaptive immunity systems allowed NMD and the motif-triggered mechanisms to be efficiently repurposed for regulation of endogenous cellular transcripts. This scenario explains the rapid emergence of archetypical mRNA destabilization pathways in eukaryotes and argues that other aspects of post-transcriptional gene regulation in this lineage might have been derived through a similar exaptation route. mRNA turnover in eukaryotes is remarkably different from its prokaryotic counterparts and possible reasons underlying this divergence remain unclear. Here we propose that eukaryotic mRNA destabilization pathways evolved as a part of host defense against RNA pathogens and were subsequently repurposed for post-transcriptional regulation of cell-encoded genes.

Beschreibung: Soma to germline inheritance of extrachromosomal genetic information. Non-Mendelian transgenerational inheritance is a growingly recognized phenomenon, yet still elusive in its molecular nature . On pages 726–733 of this issue, Corrado Spadafora proposes a model, whereby extrachromosomal genetic information released form somatic cells can cross the Weismann barrier and become internalized in epididymal spermatozoa, which thereafter mediate the acquisition of new traits in the offspring at fertilization. The sperm endogenous reverse transcriptase (RT) plays a key role in developmental control. Sperm cells therefore act as recipients, and at the same time transgenerational vectors, of somatically derived genetic information, which they pass to the next generation in a non chromosomally-integrated form, yet with the potential to modify the fate of the developing embryos.

Beschreibung: The conventional approach to developing disease-modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic driver of age-of-onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals. Different factors may determine the onset of a neurodegenerative disease versus its progression. Thus, treatments aiming to slow progression based on targets which determine onset may have less efficacy with increased disease duration.

Beschreibung: Coiled-coils are found in proteins throughout all three kingdoms of life. Coiled-coil domains of some proteins are almost invariant in sequence and length, betraying a structural and functional role for amino acids along the entire length of the coiled-coil. Other coiled-coils are divergent in sequence, but conserved in length, thereby functioning as molecular spacers. In this capacity, coiled-coil proteins influence the architecture of organelles such as centrioles and the Golgi, as well as permit the tethering of transport vesicles. Specialized coiled-coils, such as those found in motor proteins, are capable of propagating conformational changes along their length that regulate cargo binding and motor processivity. Coiled-coil domains have also been identified in enzymes, where they function as molecular rulers, positioning catalytic activities at fixed distances. Finally, while coiled-coils have been extensively discussed for their potential to nucleate and scaffold large macromolecular complexes, structural evidence to substantiate this claim is relatively scarce. Supercoiling of α-helices gives rise to coiled-coil structures of theoretically infinite length. The tunable length and mechanical properties of coiled-coils make them suitable for a wide variety of functions in the cell including molecular rulers or spacers, molecular tethers, and for communicating information along their length.

Beschreibung: Observing adaptive evolution is difficult. In the fossil record, phenotypic evolution happens much more slowly than in artificial selection experiments or in experimental evolution. Yet measures of selection on phenotypic traits, with high heritabilities, suggest that phenotypic evolution should also be rapid in the wild, and this discrepancy often remains even after accounting for correlations between different traits (i.e. making predictions using the multivariate version of the breeder's equation). Are fitness correlations with quantitative traits adequate measures of selection in the wild? We should instead view fitnesses as average properties of genotypes, while acknowledging that they can be environment-dependent. Populations will tend to remain at fitness equilibria, once these are attained, and phenotypes will then be stable. Thus, studying the causes of adaptive change at a genotypic rather than phenotypic level may reveal that, typically, it is occurring too slowly to be easily observed. Measured phenotypic evolutionary rates are high under artificial selection and in changed environments, but are low when environments are constant and are very low over paleontological time. Additive genetic variance (heritability) and apparent selection predict high rates of phenotypic evolution, which is not seen. Why?

Beschreibung: One of the main questions in the use of genome editing tools is their specificity and the degree of possible off-target events. The cover shows two of the protein scaffolds commonly used for this purpose, TALE and Cas9, targeting a DNA site for the generation of specific cleavage. As discussed by Stella and Montoya in this issue, a key element in this genome modification strategy is whether DNA binding has been achieved accurately to generate the desired modification in the right genomic site.

Beschreibung: Cancer is an evolutionary and ecological process in which complex interactions between tumour cells and their environment share many similarities with organismal evolution. Tumour cells with highest adaptive potential have a selective advantage over less fit cells. Naturally occurring transmissible cancers provide an ideal model system for investigating the evolutionary arms race between cancer cells and their surrounding micro-environment and macro-environment. However, the evolutionary landscapes in which contagious cancers reside have not been subjected to comprehensive investigation. Here, we provide a multifocal analysis of transmissible tumour progression and discuss the selection forces that shape it. We demonstrate that transmissible cancers adapt to both their micro-environment and macro-environment, and evolutionary theories applied to organisms are also relevant to these unique diseases. The three naturally occurring transmissible cancers, canine transmissible venereal tumour (CTVT) and Tasmanian devil facial tumour disease (DFTD) and the recently discovered clam leukaemia, exhibit different evolutionary phases: (i) CTVT, the oldest naturally occurring cell line is remarkably stable; (ii) DFTD exhibits the signs of stepwise cancer evolution; and (iii) clam leukaemia shows genetic instability. While all three contagious cancers carry the signature of ongoing and fairly recent adaptations to selective forces, CTVT appears to have reached an evolutionary stalemate with its host, while DFTD and the clam leukaemia appear to be still at a more dynamic phase of their evolution. Parallel investigation of contagious cancer genomes and transcriptomes and of their micro-environment and macro-environment could shed light on the selective forces shaping tumour development at different time points: during the progressive phase and at the endpoint. A greater understanding of transmissible cancers from an evolutionary ecology perspective will provide novel avenues for the prevention and treatment of both contagious and non-communicable cancers. Transmissible cancers are ideal to investigate the evolutionary arms race between cancer cells and their surrounding environment. While all three contagious cancers show ongoing adaptations to selective forces, canine transmissible venereal tumour has reached an evolutionary stalemate with its host, while devil facial tumor disease and clam leukaemia are still in a more dynamic phase of their evolution.

Beschreibung: Entry into mitosis is driven by the activity of kinases, which phosphorylate over 7000 proteins on multiple sites. For cells to exit mitosis and segregate their genome correctly, these phosphorylations must be removed in a specific temporal order. This raises a critical and important question: how are specific phosphorylation sites on an individual protein removed? Traditionally, the temporal order of dephosphorylation was attributed to decreasing kinase activity. However, recent evidence in human cells has identified unique patterns of dephosphorylation during mammalian mitotic exit that cannot be fully explained by the loss of kinase activity. This suggests that specificity is determined in part by phosphatases. In this review, we explore how the physicochemical properties of an individual phosphosite and its surrounding amino acids can affect interactions with a phosphatase. These positive and negative interactions in turn help determine the specific pattern of dephosphorylation required for correct mitotic exit. During mitotic exit, phosphatases reverse thousands of phosphorylation events in a specific temporal order to ensure that cell division occurs correctly. This review explores how the physicochemical properties of the phosphosite and surrounding amino acids affect interactions with phosphatase/s and help determine the dephosphorylation of individual phosphorylation sites during mitotic exit.

Beschreibung: Cellular senescence is an anti-proliferative program that restricts the propagation of cells subjected to different kinds of stress. Cellular senescence was initially described as a cell-autonomous tumor suppressor mechanism that triggers an irreversible cell cycle arrest that prevents the proliferation of damaged cells at risk of neoplastic transformation. However, discoveries during the last decade have established that senescent cells can also impact the surrounding tissue microenvironment and the neighboring cells in a non-cell-autonomous manner. These non-cell-autonomous activities are, in part, mediated by the selective secretion of extracellular matrix degrading enzymes, cytokines, chemokines and immune modulators, which collectively constitute the senescence-associated secretory phenotype. One of the key functions of the senescence-associated secretory phenotype is to attract immune cells, which in turn can orchestrate the elimination of senescent cells. Interestingly, the clearance of senescent cells seems to be critical to dictate the net effects of cellular senescence. As a general rule, the successful elimination of senescent cells takes place in processes that are considered beneficial, such as tumor suppression, tissue remodeling and embryonic development, while the chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging. Nevertheless, exceptions to this rule may exist. Now that cellular senescence is in the spotlight for both anti-cancer and anti-aging therapies, understanding the precise underpinnings of senescent cell removal will be essential to exploit cellular senescence to its full potential. Senescent cells secrete a variety of cytokines, immune modulators and extracellular matrix degrading enzymes, which constitute the senescence-associated secretory phenotype (SASP). The SASP can direct immune cells for senescent cell clearance, promoting tissue homeostasis, tumor suppression and rejuvenation. In the absence of clearance, SASP can promote tumorigenesis, fibrosis and aging.

Beschreibung: In the last 10 years, we have witnessed a blooming of targeted genome editing systems and applications. The area was revolutionized by the discovery and characterization of the transcription activator-like effector proteins, which are easier to engineer to target new DNA sequences than the previously available DNA binding templates, zinc fingers and meganucleases. Recently, the area experimented a quantum leap because of the introduction of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (Cas) system (clustered regularly interspaced short palindromic sequence). This ribonucleoprotein complex protects bacteria from invading DNAs, and it was adapted to be used in genome editing. The CRISPR ribonucleic acid (RNA) molecule guides to the specific DNA site the Cas9 nuclease to cleave the DNA target. Two years and more than 1000 publications later, the CRISPR-Cas system has become the main tool for genome editing in many laboratories. Currently the targeted genome editing technology has been used in many fields and may be a possible approach for human gene therapy. Furthermore, it can also be used to modifying the genomes of model organisms for studying human pathways or to improve key organisms for biotechnological applications, such as plants, livestock genome as well as yeasts and bacterial strains. The area of genome editing using engineered nucleases is growing extremely fast because of platforms such as Transcription Activator-Like Effector (TALE) and CRIPSR-Cas9. However, a reliable method to assess the off-target effect of these engineered nucleases is still missing. This review comments the existing techniques to measure off-target effects.

Beschreibung: Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays multiple and essential roles during the cell division cycle. Its inhibition in cultured cells leads to severe mitotic aberrancies and cell death. Whereas previous reports suggested that Plk1 depletion in mice leads to a non-mitotic arrest in early embryos, we show here that the bi-allelic Plk1 depletion in mice certainly results in embryonic lethality due to extensive mitotic aberrations at the morula stage, including multi- and mono-polar spindles, impaired chromosome segregation and cytokinesis failure. In addition, the conditional depletion of Plk1 during mid-gestation leads also to severe mitotic aberrancies. Our data also confirms that Plk1 is completely dispensable for mitotic entry in vivo. On the other hand, Plk1 haploinsufficient mice are viable, and Plk1-heterozygous fibroblasts do not harbor any cell cycle alterations. Plk1 is overexpressed in many human tumors, suggesting a therapeutic benefit of inhibiting Plk1, and specific small-molecule inhibitors for this kinase are now being evaluated in clinical trials. Therefore, the different Plk1 mouse models here presented are a valuable tool to reexamine the relevance of the mitotic kinase Plk1 during mammalian development and animal physiology. Two different mouse strains, a classical gene-trapping KO and a conditional KO by Cre recombinase excision, demonstrate that the mitotic kinase Plk1 is essential at any stage of the embryonic development, and its depletion leads to mitotic aberrancies and embryonic death. Instead, Plk1 haploinsufficient mice do not show any alteration.

Beschreibung: Human pluripotent stem cells (hPSCs) have the potential to fundamentally change the way that we go about treating and understanding human disease. Despite this extraordinary potential, these cells also have an innate capability to form tumors in immunocompromised individuals when they are introduced in their pluripotent state. Although current therapeutic strategies involve transplantation of only differentiated hPSC derivatives, there is still a concern that transplanted cell populations could contain a small percentage of cells that are not fully differentiated. In addition, these cells have been frequently reported to acquire genetic alterations that, in some cases, are associated with certain types of human cancers. Here, we try to separate the panic from reality and rationally evaluate the true tumorigenic potential of these cells. We also discuss a recent study examining the effect of culture conditions on the genetic integrity of hPSCs. Finally, we present a set of sensible guidelines for minimizing the tumorigenic potential of hPSC-derived cells. © 2016 The Authors. Inside the Cell published by Wiley Periodicals, Inc. hPSC-derived cells have the potential to cause tumors during cell therapy but simple steps can be taken to minimize the risk. 1) Genomic analysis to ensure the cells' genetic integrity. 2) Purging contaminating undifferentiated and progenitor cells after differentiation. 3) In vivo testing to demonstrate that the cells aren't tumorigenic.

Beschreibung: Disabled-2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell–cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab-2 controls the extent of platelet aggregation through various motifs within its N-terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside-out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin α IIb β 3 receptor binding and, thus, modulates outside-in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell–cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences. Disabled-2 (Dab2) is a multimodular scaffold protein and a putative tumor suppressor involved in a wide array of physiological processes. This review highlights the latest findings involving Dab2 in protein trafficking, immune response, and development, placing emphasis on the recently reported modulatory role of Dab2 in cell-cell interactions.

Beschreibung: Depletion of mitochondrial endo/exonuclease G-like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G-like-depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G-like depletion. Interestingly, PE-induced atrial natriuretic peptide (ANP) gene expression was completely abolished in endo/exonuclease G-like-depleted cells, suggesting a reverse signaling function of endo/exonuclease G-like. Endo/exonuclease G-like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G-like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G-like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G-like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death. Mitochondrial Endonuclease G-like-1 (EXOG) modulates mitochondrial respiration and hypertrophy in cardiomyocytes. Here we show that pathological stimulation of EXOG depleted cardiomyocytes results in a diminished mitochondrial reserve capacity, which marks subsequent cell death. EXOG is therefore essential in pathological stress adaptation and to maintain cell viability.

Beschreibung: Positive transcription elongation factor b (P-TEFb), which comprises cyclin-dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P-TEFb is required for productive elongation of transcription of protein-coding genes by RNA polymerase II (pol II). In addition, P-TEFb-mediated phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P-TEFb could be effective anti-viral agents. Many viruses subvert transcription elongation factor b (P-TEFb) function to facilitate viral gene expression. P-TEFb is integral to the replication of a range of viruses, including herpes simplex virus, Kaposi sarcoma-associated herpesvirus, human cytomegalovirus, Epstein–Barr virus, human immunoficiency virus, human t-lymphotropic virus type 1, adenovirus, influenza A and dengue virus.

Beschreibung: Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1-deficient zebrafish mutant, nrc a14 . We found that loss of SynJ1 leads to specific accumulation of late endosomes and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate because of a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrc a14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5'phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P 2 regulator, Arf6, rescued the disrupted trafficking pathways in nrc a14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P 2 participates in autophagy in a neuronal cell type. Loss of synaptojanin 1 (SynJ1) causes late endosomal and autophagic defects in cone photoreceptors. Modulating the activity of the PI(4,5)P 2 regulator Arf6a rescues autophagy defects in the absence of SynJ1. We propose that SynJ1 negatively regulates the formation of autophagosome precursors through actions on membrane PI(4,5)P 2 .

Beschreibung: Enhancers can stimulate transcription by a number of different mechanisms which control different stages of the transcription cycle of their target genes, from recruitment of the transcription machinery to elongation by RNA polymerase. These mechanisms may not be mutually exclusive, as a single enhancer may act through different pathways by binding multiple transcription factors. Multiple enhancers may also work together to regulate transcription of a shared target gene. Most of the evidence supporting different enhancer mechanisms comes from the study of single genes, but new high-throughput experimental frameworks offer the opportunity to integrate and generalize disparate mechanisms identified at single genes. This effort is especially important if we are to fully understand how sequence variation within enhancers contributes to human disease. Enhancers are regulatory elements that bind transcription factors and activate expression of their target genes by stimulating specific steps in the RNA polymerase II transcription cycle. Here we review the mechanisms of enhancer action and highlight opportunities for new insights from high-throughput experimental technologies such as massively parallel reporter assays.

Beschreibung: 5-methylcytosine (5mC) was long thought to be the only enzymatically created modified DNA base in mammalian cells. The discovery of 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine as reaction products of the TET family 5mC oxidases has prompted extensive searches for proteins that specifically bind to these oxidized bases. However, only a few of such “reader” proteins have been identified and verified so far. In this review, we discuss potential biological functions of oxidized 5mC as well as the role the presumed reader proteins may play in interpreting the genomic signals of 5mC oxidation products. Oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine by TET proteins can lead to DNA demethylation. However, the oxidized 5mC bases are rather stable and may function as negative marks for 5mC readers. Intriguingly, proteins that bind to oxidized 5mC have now been identified and characterized by structural studies.

Beschreibung: On pages 618–626 , Schmidt et al. discuss the concept of cofactor squelching in light of recent evidence from genome-wide studies indicating that such competition for a limiting amount of coactivators is a general mechanism of transcriptional repression by signal-dependent transcription factors (TFs). They further discuss how TF cooperativity in so-called hotspots and super-enhancers may sensitize these enhancers to cofactor squelching. The cover illustrates how signal dependent TFs can be regarded as the ‘Robin Hoods’ of the genome, redistributing cofactors (gold coins) from the wealthy super-enhancers (stacks of gold coins). Cover design: Andreas N. Grøntved.

Beschreibung: Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self-renewal and differentiation. In particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation-specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine. Computational modeling of heterogeneity in pluripotent cells, integrating single-cell measurements at the signaling, transcriptional, and epigenetics levels will be essential for understanding the regulation of self-renewal and differentiation. Here we discuss on how computational modeling could be useful for developing efficient strategies for improving the efficiency and fidelity of differentiation.

Beschreibung: Comparative mapping and sequencing show that turnover of sex determining genes and chromosomes, and sex chromosome rearrangements, accompany speciation in many vertebrates. Here I review the evidence and propose that the evolution of therian mammals was precipitated by evolution of the male-determining SRY gene, defining a novel XY sex chromosome pair, and interposing a reproductive barrier with the ancestral population of synapsid reptiles 190 million years ago (MYA). Divergence was reinforced by multiple translocations in monotreme sex chromosomes, the first of which supplied a novel sex determining gene. A sex chromosome-autosome fusion may have separated eutherians (placental mammals) from marsupials 160 MYA. Another burst of sex chromosome change and speciation is occurring in rodents, precipitated by the degradation of the Y. And although primates have a more stable Y chromosome, it may be just a matter of time before the same fate overtakes our own lineage. Also watch the video abstract . Sex chromosome turnover is rare in mammals, but major changes in sex chromosomes characterise the three branches of mammals. Here I propose that sex chromosome turnover following SRY evolution, as well as XY-autosome fusions and translocations, interposed mating barriers that precipitated divergence of monotremes, marsupials and placental mammals.

Beschreibung: Both W9 and OP3-4 were known to bind the receptor activator of NF-κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide-induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3-4 accelerated BMP-2-induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL-binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP-2-induced bone regeneration by the RANKL-binding peptides. Micro CT and fluorescent images revealed that two RANKL-binding peptides, W9 and OP3-4, could equally accelerate BMP-2-induced local bone regeneration in a murine calvarial defect model. The yellow line shows the site of the reconstruction images in the middle panel. White lines show the size of the original defect.

Beschreibung: Frequent evolutionary birth and death events have created a large quantity of biologically important, lineage-specific DNA within mammalian genomes. The birth and death of DNA sequences is so frequent that the total number of these insertions and deletions in the human population remains unknown, although there are differences between these groups, e.g. transposable elements contribute predominantly to sequence insertion. Functional turnover – where the activity of a locus is specific to one lineage, but the underlying DNA remains conserved – can also drive birth and death. However, this does not appear to be a major driver of divergent transcriptional regulation. Both sequence and functional turnover have contributed to the birth and death of thousands of functional promoters in the human and mouse genomes. These findings reveal the pervasive nature of evolutionary birth and death and suggest that lineage-specific regions may play an important but previously underappreciated role in human biology and disease. Lineage-specific elements within mammalian genomes have been created by evolutionary birth and death events, which are driven by frequent sequence and functional turnover. Regulatory elements, such as promoters and enhancers, are particularly evolutionarily volatile but their association with divergent transcription and human biology and disease is as yet unclear.

Beschreibung: Mitotic entry and exit are switch-like transitions that are driven by the activation and inactivation of Cdk1 and mitotic cyclins. This simple on/off reaction turns out to be a complex interplay of various reversible reactions, feedback loops, and thresholds that involve both the direct regulators of Cdk1 and its counteracting phosphatases. In this review, we summarize the interplay of the major components of the system and discuss how they work together to generate robustness, bistability, and irreversibility. We propose that it may be beneficial to regard the entry and exit reactions as two separate reversible switches that are distinguished by differences in the state of phosphatase activity, mitotic proteolysis, and a dramatic rearrangement of cellular components after nuclear envelope breakdown, and discuss how the major Cdk1 activity thresholds could be determined for these transitions. A complex cell cycle control network is responsible for mitotic entry and exit. This system is based on Cdk1 activation and inactivation and behaves like a bistable switch. We are discussing the various control elements in this system and their contribution to the thresholds that ultimately determine bistability.

Beschreibung: Eukaryotic mRNAs are monocistronic, and therefore mechanisms exist that coordinate the synthesis of multiprotein complexes in order to obtain proper stoichiometry at the appropriate intracellular locations. RNA-binding proteins containing low-complexity sequences are prone to generate liquid droplets via liquid-liquid phase separation, and in this way create cytoplasmic assemblages of functionally related mRNAs. In a recent iCLIP study, we showed that the Drosophila RNA-binding protein Imp, which exhibits a C-terminal low-complexity sequence, increases the formation of F-actin by binding to 3′ untranslated regions of mRNAs encoding components participating in F-actin biogenesis. We hypothesize that phase transition is a mechanism the cell employs to increase the local mRNA concentration considerably, and in this way synchronize protein production in cytoplasmic territories, as discussed in the present review. RNA-binding proteins containing low-complexity sequences are prone to generate cytoplasmic assemblages of functionally related mRNAs within liquid droplets. Such a partitioning mechanism coordinates local post-transcriptional regulation and ensures proximity of synthesized proteins in response to environmental cues, as illustrated for F-actin biogenesis during cellular migration.

Beschreibung: Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel , is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to CytOx, causing inhibition. In times of stress, ATP-dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased. ATP-binding inhibits Cytochrome c Oxidase, and ROS formation is decreased. This mechanism depends on the quantity of electron transfer to the Heme aa3 of CytOx. In times of stress, ATP-dependent inhibition is switched off and activity of CytOx is exclusively determined by the membrane potential, leading to increased ROS production.

Beschreibung: Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro-environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity of mechanistic target of rapamycin complex 2 (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies. We propose that in glioblastoma, and possibly other cancers, abundant glucose or acetate, which are readily available to tumor cells in their native environment, facilitate biochemical modification of a core component of the growth factor receptor signaling pathway, mTOR complex 2, driving growth and rendering tumors resistant to drugs that target upstream components of growth factor signaling pathways.

Beschreibung: Cells live in dynamic environments that necessitate perpetual adaptation. Since cells have limited resources to monitor external inputs, they are required to maximize the information content of perceived signals. This challenge is not unique to microscopic life: Animals use senses to perceive inputs and adequately respond. Research showed that sensory-perception is actively shaped by learning and expectation allowing internal cognitive models to “fill in the blanks” in face of limited information. We propose that cells employ analogous strategies and use internal models shaped through the long process of evolutionary adaptation. Given this perspective, we postulate that cells are prone to “misperceptions,” analogous to visual illusions, leading them to incorrectly decode patterns of inputs that lie outside of their evolutionary experience. Mapping cellular misperception can serve as a fundamental approach for dissecting regulatory networks and could be harnessed to modulate cell behavior, a potentially new avenue for therapy. Cells use regulatory networks to guide their responses after changes in their environments. In extreme cases, the mapping between external stimuli and downstream responses can be incorrect and culminate in adverse fitness effects. We propose that the mapping cellular “misperceptions” can serve as a fundamental approach for dissecting regulatory networks.

Beschreibung: The major challenge in complex disease genetics is to understand the fundamental features of this complexity and why functional alterations at multiple independent genes conspire to lead to an abnormal phenotype. We hypothesize that the various genes involved are all functionally united through gene regulatory networks (GRN), and that mutant phenotypes arise from the consequent perturbation of one or more rate-limiting steps that affect the function of the entire GRN. Understanding a complex phenotype thus entails unraveling the details of each GRN, namely, the transcription factors that bind to cis regulatory elements affected by sequence variants altering transcription of specific genes, and their mutual feedback relationships. These GRNs can be identified through their rate-limiting steps and are best uncovered by genomic analyses of rare, extreme phenotype families, thus providing a coherent molecular basis to complex traits and disorders. Gene regulatory network and its postulated effects on a binary phenotype which is sex-dependent. Phenotype altering variants in a rate-limiting (with respect to GRN activity) gene ( X ), in contrast to others (A, B, C), will affect the group with the higher trait values because they will have larger impact.

Beschreibung: Mitochondria exist in large numbers per cell. Therefore, the strength of natural selection on individual mtDNAs for their contribution to cellular fitness is weak whereas the strength of selection in favor of mtDNAs that increase their own replication without regard for cellular functions is strong. This problem has been solved for most mitochondrial genes by their transfer to the nucleus but a few critical genes remain encoded by mtDNA. Organisms manage the evolution of mtDNA to prevent mutational decay of essential services mitochondria provide to their hosts. Bottlenecks of mitochondrial numbers in female germlines increase the homogeneity of mtDNAs within cells and allow intraorganismal selection to eliminate cells with low quality mitochondria. Mechanisms of intracellular “quality control” allow direct selection on the competence of individual mtDNAs. These processes maintain the integrity of mtDNAs within the germline but are inadequate to indefinitely maintain mitochondrial function in somatic cells. Mitochondria are domesticated prokaryotes that reside in large herds within cells. Female germ cells are the stud farms that stock the herds of the next generation of bodies. Mechanisms of quality control within cells and selection among oogonia and oocytes are the mechanisms of “selective breeding” that maintain herd quality.

Beschreibung: The mechanical properties of vertebrate cells are largely defined by the system of intermediate filaments (IF). As part of a dense network, IF polymers are constantly rearranged and relocalized in the cell to fulfill their duty as cells change shape, migrate, or divide. With the development of new imaging technologies, such as photoconvertible proteins and super-resolution microscopy, a new appreciation for the complexity of IF dynamics has emerged. This review highlights new findings about the transport of IF, the remodeling of filaments by a process of severing and re-annealing, and the subunit exchange that occurs between filament precursors and a soluble pool of IF. We will also discuss the unique dynamic features of the keratin IF network. Finally, we will speculate about how the dynamic properties of IF are related to their functions. The dynamics of intermediate filaments include microtubule-dependent transport, end-to-end fusion, severing, and subunit exchange. These processes can now be observed in real time using improved imaging technologies and photoconvertible probes. Dynamics may balance the forms of intermediate filaments (soluble, ULF, or filamentous) that could play differential roles in the cell.

Beschreibung: The phosphorelay of Bacillus subtilis , a kinase cascade that activates master regulator Spo0A ∼ P in response to starvation signals, is the core of a large network controlling the cell's decision to differentiate into sporulation and other phenotypes. This article reviews recent advances in understanding the origins and purposes of the complex dynamical behavior of the phosphorelay, which pulses with peaks of activity coordinated with the cell cycle. The transient imbalance in the expression of two critical genes caused by their strategic placement at opposing ends of the chromosome proved to be the key for this pulsed behavior. Feedback control loops in the phosphorelay use these pulses to implement a timer mechanism, which creates several windows of opportunity for phenotypic transitions over multiple generations. This strategy allows the cell to coordinate multiple differentiation programs in a decision process that fosters phenotypic diversity and adapts to current conditions. The phosphorelay of Bacillus subtilis controls differentiation into sporulation and other phenotypes in response to starvation. This kinase cascade pulses with peaks of activity coordinated with the cell cycle. We review the role of this complex dynamical behavior in timing cell fate decisions and generating phenotypic diversity at the colony level.

Beschreibung: Much of what we understand about heterochromatin formation in mammals has been extrapolated from forward genetic screens for modifiers of position-effect variegation (PEV) in the fruit fly Drosophila melanogaster . The recent identification of the HUSH (Human Silencing Hub) complex suggests that more recent evolutionary developments contribute to the mechanisms underlying PEV in human cells. Although HUSH-mediated repression also involves heterochromatin spreading through the reading and writing of the repressive H3K9me3 histone modification, clear orthologues of HUSH subunits are not found in Drosophila but are conserved in vertebrates. Here we compare the insights into the mechanisms of PEV derived from genetic screens in the fly, the mouse and in human cells, review what is currently known about the HUSH complex and discuss the implications of HUSH-mediated silencing for viral latency. Future studies will provide mechanistic insight into HUSH complex function and reveal the relationship between HUSH and other epigenetic silencing complexes. Chromosomal position-effects have been investigated through Drosophila screens for modifiers of position-effect variegation. An analogous gene-trap mutagenesis screen in near-haploid human KBM7 cells identified HUSH, an epigenetic silencing complex composed of FAM208A/TASOR, MPP8 and Periphilin, which mediates heterochromatin spreading through SETDB1 recruitment and deposition of the repressive H3K9me3 histone modification.

Beschreibung: Hindbrain development is orchestrated by a vertebrate gene regulatory network that generates segmental patterning along the anterior–posterior axis via Hox genes. Here, we review analyses of vertebrate and invertebrate chordate models that inform upon the evolutionary origin and diversification of this network. Evidence from the sea lamprey reveals that the hindbrain regulatory network generates rhombomeric compartments with segmental Hox expression and an underlying Hox code. We infer that this basal feature was present in ancestral vertebrates and, as an evolutionarily constrained developmental state, is fundamentally important for patterning of the vertebrate hindbrain across diverse lineages. Despite the common ground plan, vertebrates exhibit neuroanatomical diversity in lineage-specific patterns, with different vertebrates revealing variations of Hox expression in the hindbrain that could underlie this diversification. Invertebrate chordates lack hindbrain segmentation but exhibit some conserved aspects of this network, with retinoic acid signaling playing a role in establishing nested domains of Hox expression. A developmental gene regulatory network couples Hox gene expression to hindbrain segmentation in all vertebrates. Evidence from jawless vertebrates and invertebrate chordates indicates that this pan-vertebrate network originated from an ancient anterior–posterior patterning program. Cross-species comparisons suggest diversification in the network may contribute to neuro-anatomical differences between vertebrates.

Beschreibung: Metagenomics bears upon all aspects of microbiology, including our understanding of mitochondrial and eukaryote origin. Recently, ribosomal protein phylogenies show the eukaryote host lineage – the archaeal lineage that acquired the mitochondrion – to branch within the archaea. Metagenomic studies are now uncovering new archaeal lineages that branch more closely to the host than any cultivated archaea do. But how do they grow? Carbon and energy metabolism as pieced together from metagenome assemblies of these new archaeal lineages, such as the Deep Sea Archaeal Group (including Lokiarchaeota) and Bathyarchaeota, do not match the physiology of any cultivated microbes. Understanding how these new lineages live in their environment is important, and might hold clues about how mitochondria arose and how the eukaryotic lineage got started. Here we look at these exciting new metagenomic studies, what they say about archaeal physiology in modern environments, how they impact views on host-mitochondrion physiological interactions at eukaryote origin. Newly identified archaeal lineages make their living in the utter darkness of black-smoker-land on the sea bed using a uniquely ancient mechanism: Methanogenesis in the context of their hydrogen-dependent energy metabolism. Molecular phylogenetics increasingly suggests that, these are the successors of ancient archaea that teamed up with alpha-proteobacterium to produce the first eukaryotes; and their thirst for hydrogen gives us clues as to the physiological interaction between host and proto-mitochondrion.

Beschreibung: Why do cells age? Recent advances show that the cytoplasm is organized into many membrane-less compartments via a process known as phase separation, which ensures spatiotemporal control over diffusion-limited biochemical reactions. Although phase separation is a powerful mechanism to organize biochemical reactions, it comes with the trade-off that it is extremely sensitive to changes in physical-chemical parameters, such as protein concentration, pH, or cellular energy levels. Here, we highlight recent findings showing that age-related neurodegenerative diseases are linked to aberrant phase transitions in neurons. We discuss how these aberrant phase transitions could be tied to a failure to maintain physiological physical-chemical conditions. We generalize this idea to suggest that the process of cellular aging involves a progressive loss of the organization of phase-separated compartments in the cytoplasm. Phase transitions are emerging as a new mechanism of intracellular organization. Here, we hypothesize that age-related fluctuations in physical-chemical parameters trigger aberrant phase transitions with a consequent loss of control over intracellular organization. Our concept may explain many hallmarks of aging and the increasing risk of disease with age.

Beschreibung: Stable heavy isotopes co-exist with their lighter counterparts in all elements commonly found in biology. These heavy isotopes represent a low natural abundance in isotopic composition but impose great retardation effects in chemical reactions because of kinetic isotopic effects (KIEs). Previous isotope analyses have recorded pervasive enrichment or depletion of heavy isotopes in various organisms, strongly supporting the capability of biological systems to distinguish different isotopes. This capability has recently been found to lead to general decline of heavy isotopes in metabolites during yeast aging. Conversely, supplementing heavy isotopes in growth medium promotes longevity. Whether this observation prevails in other organisms is not known, but it potentially bears promise in promoting human longevity. Our current hypothesis states that aging progression is accompanied with a general decline in the living organism's ability to incorporate heavy isotopes. Averting this decline would retard aging or promote longevity. The green blocks indicate the effective relative abundance of common heavy isotopes in human bodies.

Beschreibung: As crucial interface organs gut and skin have much in common. Therefore it is unsurprising that several gut pathologies have skin co-morbidities. Nevertheless, the reason for this remains ill explored, and neither mainstream gastroenterology nor dermatology research have systematically investigated the ‘gut-skin axis'. Here, in reviewing the field, we propose several mechanistic levels on which gut and skin may interact under physiological and pathological circumstances. We focus on the gut microbiota, with its huge metabolic capacity, and the role of dietary components as potential principle actors along the gut-skin axis. We suggest that metabolites from either the diet or the microbiota are skin accessible. After defining open key questions around the nature of these metabolites, how they are sensed, and which cutaneous changes they can induce, we propose that understanding of these pathways will lead to novel therapeutic strategies based on targeting one organ to improve the health of the other. The gut and skin engage in bidirectional mechanisms of communication. These mechanisms include, the microbiota, diet, neuroendocrine and immune systems and the central nervous system. It is therefore not surprising that any malfunction along this gut-skin axis can have profound effects on both organs. This is exemplified in disease.

Beschreibung: SUMOylation during regulation of DNA replication . On pages 863–868 , Veronique Smits and Raimundo Freire discuss the implications of a recent publication demonstrating a novel role for USP7/HAUSP during DNA replication. USP7 was shown to be enriched at sites of DNA replication and is required for replicationfork progression and the firing of new origins. USP7 contributes to these processes by removing ubiquitin from SUMOylated proteins at the replication fork, thereby creating a SUMO-rich and Ub-poor environment at the replisome. The cover shows a model of USP7 functioning as SUMO-DUB at the replication fork, with possible target proteins and other enzymes involved. SUMO and ubiquitin molecules are represented as small blue and yellow ovals, respectively.

Beschreibung: Melatonin is a hormone with complex roles in the pathogenesis of autoimmune disorders. Over the years, it has become clear that melatonin may exacerbate some autoimmune conditions, whereas it alleviates others such as multiple sclerosis. Multiple sclerosis is an autoimmune disorder characterized by a dysregulated immune response directed against the central nervous system. Indeed, the balance between pathogenic CD4 + T cells secreting IFN-γ (T H 1) or IL-17 (T H 17); and FoxP3 + regulatory T cells and IL-10 + type 1 regulatory T cells (Tr1 cells) is thought to play an important role in disease activity. Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin-triggered signaling pathways are potential targets for therapeutic intervention. Here, we review the available data on the effects of melatonin on immune processes relevant for MS and discuss its therapeutic potential. Melatonin synthesis is stimulated by darkness and inhibited by light. Thus, melatonin levels are seasonal with higher levels in fall and winter. Recently, melatonin levels have been linked to multiple sclerosis disease activity. Melatonin may affect multiple sclerosis and potentially other autoimmune disorders by boosting or suppressing several immune cell subsets.

Beschreibung: Recent evidence indicates that inhibition of protein translation may be a common pathogenic mechanism for peripheral neuropathy associated with mutant tRNA synthetases (aaRSs). aaRSs are enzymes that ligate amino acids to their cognate tRNA, thus catalyzing the first step of translation. Dominant mutations in five distinct aaRSs cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, characterized by length-dependent degeneration of peripheral motor and sensory axons. Surprisingly, loss of aminoacylation activity is not required for mutant aaRSs to cause CMT. Rather, at least for some mutations, a toxic-gain-of-function mechanism underlies CMT-aaRS. Interestingly, several mutations in two distinct aaRSs were recently shown to inhibit global protein translation in Drosophila models of CMT-aaRS, by a mechanism independent of aminoacylation, suggesting inhibition of translation as a common pathogenic mechanism. Future research aimed at elucidating the molecular mechanisms underlying the translation defect induced by CMT-mutant aaRSs should provide novel insight into the molecular pathogenesis of these incurable diseases. Mutations in five distinct tRNA synthetase (aaRS) genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. At least some CMT-causing mutations do not affect the tRNA aminoacylation activity. Here, the hypothesis is presented that mutant aaRSs may inhibit protein translation through a gain-of-toxic-function mechanism, possibly constituting a common pathogenic mechanism for CMT-aaRS.

Beschreibung: DNA replication is both highly conserved and controlled. Problematic DNA replication can lead to genomic instability and therefore carcinogenesis. Numerous mechanisms work together to achieve this tight control and increasing evidence suggests that post-translational modifications (phosphorylation, ubiquitination, SUMOylation) of DNA replication proteins play a pivotal role in this process. Here we discuss such modifications in the light of a recent article that describes a novel role for the deubiquitinase (DUB) USP7/HAUSP in the control of DNA replication. USP7 achieves this function by an unusual and novel mechanism, namely deubiquitination of SUMOylated proteins at the replication fork, making USP7 also a SUMO DUB (SDUB). This work extends previous observations of increased levels of SUMO and low levels of ubiquitin at the on-going replication fork. Here, we discuss this novel study, its contribution to the DNA replication and genomic stability field and what questions arise from this work. Post-translational modifications are important in the regulation of DNA replication. USP7/HAUSP was recently shown to contribute to this process by removing ubiquitin from SUMOylated proteins at the replication fork. Smits and Freire speculate here on modified substrate(s), other enzymes involved and mechanistic details of this novel function of SDUB USP7.

Beschreibung: This review portraits FK506 binding protein (FKBP) 51 as “reactivity protein” and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co-chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic stress. In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion. Also watch the video abstract . In response to environmental change, organisms adjust certain molecular circuits to cope with the new situation. This review collates the evidence linking FK506 binding protein (FKBP) 51 to molecular pathways of adaptation. Successful adaptation depends on the reactivity of these pathways that typically are organized in molecular feedback loops.

Beschreibung: Intracellular NLR ( N ucleotide-binding domain and L eucine-rich R epeat-containing) receptors are sensitive monitors that detect pathogen invasion of both plant and animal cells. NLRs confer recognition of diverse molecules associated with pathogen invasion. NLRs must exhibit strict intramolecular controls to avoid harmful ectopic activation in the absence of pathogens. Recent discoveries have elucidated the assembly and structure of oligomeric NLR signalling complexes in animals, and provided insights into how these complexes act as scaffolds for signal transduction. In plants, recent advances have provided novel insights into signalling-competent NLRs, and into the myriad strategies that diverse plant NLRs use to recognise pathogens. Here, we review recent insights into the NLR biology of both animals and plants. By assessing commonalities and differences between kingdoms, we are able to develop a more complete understanding of NLR function. NLRs mediate immunity by detecting pathogen invasion: plant NLRs recognise pathogen-secreted effectors leading to effector-triggered immunity; animal NLRs recognise pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and effectors, and activate inflammatory responses. This general diagram omits specific detail in order to emphasise the parallels between animal and plant NLRs.

Beschreibung: Development of methods to reawaken the semi-dormant regenerative potential that lies within adult human tissues would hold promise for the restoration of diseased or damaged organs and tissues. While most of the regeneration potential is suppressed in many vertebrates, including humans, during adult life, urodele amphibians (salamanders) retain their regenerative ability throughout adulthood. Studies in newts and axolotls, two salamander models, have provided significant knowledge about adult limb regeneration. In this review, we present a comparative analysis of salamander and mammalian regeneration and discuss how evolutionarily altered properties of the regenerative environment can be exploited to restore full regenerative potential in the human body. Newts and axolotls (salamanders) can effectively regenerate appendages throughout adulthood, while the regeneration potential in mammals is limited to digit tips and declines with age. Since mouse and salamander regeneration undergoes the same three phases, lessons learned from these animal models may yield new therapeutic strategies to increase human regenerative potential.

Beschreibung: Large protein assemblies are usually the effectors of major cellular processes. The intricate cell homeostasis network is divided into numerous interconnected pathways, each controlled by a set of protein machines. One of these master regulators is the CCR4-NOT complex, which ultimately controls protein expression levels. This multisubunit complex assembles around a scaffold platform, which enables a wide variety of well-studied functions from mRNA synthesis to transcript decay, as well as other tasks still being identified. Solving the structure of the entire CCR4-NOT complex will help to define the distribution of its functions. The recently published three-dimensional reconstruction of the complex, in combination with the known crystal structures of some of the components, has begun to address this. Methodological improvements in structural biology, especially in cryoelectron microscopy, encourage further structural and protein-protein interaction studies, which will advance our comprehension of the gene expression machinery. The CCR4-NOT complex, a master regulator in the control of protein expression, is involved in the regulation of RNA metabolism at many steps, from synthesis to degradation. The combination of different structural techniques (X-ray crystallography, NMR, cryoelectron microscopy) has allowed to generate a quasi-atomic model of this large macromolecular complex.

Beschreibung: When parasites have different interests in regard to how their host should behave this can result in a conflict over host manipulation, i.e. parasite induced changes in host behaviour that enhance parasite fitness. Such a conflict can result in the alteration, or even complete suppression, of one parasite's host manipulation. Many parasites, and probably also symbionts and commensals, have the ability to manipulate the behaviour of their host. Non-manipulating parasites should also have an interest in host behaviour. Given the frequency of multiple parasite infections in nature, potential conflicts of interest over host behaviour and manipulation may be common. This review summarizes the evidence on how parasites can alter other parasite's host manipulation. Host manipulation can have important ecological and medical consequences. I speculate on how a conflict over host manipulation could alter these consequences and potentially offer a new avenue of research to ameliorate harmful consequences of host manipulation. In multiple infections, different interests of parasites in regard to host behaviour and its modification by parasites (i.e. host manipulation) can result in a conflict over host manipulation. In this conflict, one parasite can modify another parasite's host manipulation altering potential ecological and medical consequences of this host manipulation.

Beschreibung: No one knows yet how to organize, in a simple yet predictive form, the knowledge concerning the anatomical, biophysical, and molecular properties of neurons that are accumulating in thousands of publications every year. The situation is not dissimilar to the state of Chemistry prior to Mendeleev's tabulation of the elements. We propose that the patterns of presence or absence of axons and dendrites within known anatomical parcels may serve as the key principle to define neuron types. Just as the positions of the elements in the periodic table indicate their potential to combine into molecules, axonal and dendritic distributions provide the blueprint for network connectivity. Furthermore, among the features commonly employed to describe neurons, morphology is considerably robust to experimental conditions. At the same time, this core classification scheme is suitable for aggregating biochemical, physiological, and synaptic information. We classify neurons using a periodic table of neuromorphological patterns, representing presynaptic axonal (red) and postsynaptic dendritic (blue) binary distributions for every neuron type (listed horizontally) across all parcels (listed vertically). Also represented are somata locations (black dots), potential excitatory (black) and inhibitory (gray) connections, and potential synapses (purple raindrops).

Beschreibung: Tumor suppressor protein 53 (p53) plays a central role in the control of genome stability, acting primarily through the transcriptional activation of stress-response genes. However, many p53 binding sites are located at genomic locations with no obvious regulatory-link to known stress-response genes. We recently discovered p53 binding sites within retrotransposon-derived elements in human and mouse subtelomeres. These retrotransposon-derived p53 binding sites protected chromosome ends through transcription activation of telomere repeat RNA, as well as through the direct modification of local chromatin structure in response to DNA damage. Based on these findings, I hypothesize that a class of p53 binding sites, including the retrotransposon-derived p53-sites found in subtlomeres, provide a primary function in genome stability by mounting a direct and local protective chromatin-response to DNA damage. I speculate that retrotransposon-derived p53 binding sites share features with telomere-repeats through an evolutionary drive to monitor and maintain genome integrity. The p53 binding sites in human subtelomeres retain features of retrotransposons. We hypothesize that retrotransposon-derived p53 binding sites function to modify local chromatin in response to genotoxic stress and enhance DNA repair activities at sites of genome fragility, such as telomere repeats.

Beschreibung: In a recent issue of Nature Communications Ukleja and co-workers reported a cryo-EM 3D reconstruction of the Ccr4-Not complex from Schizosaccharomyces pombe with an immunolocalization of the different subunits. The newly gained architectural knowledge provides cues to apprehend the functional diversity of this major eukaryotic regulator. Indeed, in the cytoplasm alone, Ccr4-Not regulates translational repression, decapping and deadenylation, and the Not module additionally plays a positive role in translation. The spatial distribution of the subunits within the structure is compatible with a model proposing that the Ccr4-Not complex interacts with the 5′ and 3′ ends of target mRNAs, allowing different functional modules of the complex to act at different stages of the translation process, possibly within a circular constellation of the mRNA. This work opens new avenues, and reveals important gaps in our understanding regarding structure and mode of function of the Ccr4-Not complex that need to be addressed in the future. The structure of the Ccr4-Not complex reveals that mRNA decay components interact with one side of the complex. The other side is available to contribute to co-translational processes. This might ensure a direct physical link between translation and mRNA decay processes, particularly if the mRNA is in a circular constellation.

Beschreibung: Altered cellular metabolism is an emerging hallmark of cancer. Accumulating recent evidence links long non-coding RNAs (lncRNAs), a still poorly understood class of non-coding RNAs, to cancer metabolism. Here we review the emerging findings on the functions of lncRNAs in cancer metabolism, with particular emphasis on how lncRNAs regulate glucose and glutamine metabolism in cancer cells, discuss how lncRNAs regulate various aspects of cancer metabolism through their cross-talk with other macromolecules, explore the mechanistic conceptual framework of lncRNAs in reprogramming metabolism in cancers, and highlight the challenges in this field. A more in-depth understanding of lncRNAs in cancer metabolism may enable the development of novel and effective therapeutic strategies targeting cancer metabolism. Altered cellular metabolism is a hallmark of cancer. The metabolic network is regulated by a myriad of metabolic enzymes. In this “Recently in press” mini-review, we discuss the emerging roles of long non-coding RNAs, the type of non-coding genes that are often described as the “dark matter” in our genome, in cancer metabolism.

Beschreibung: Genome-wide identification of transcription factor binding sites with the ChIP-seq method is an extremely important scientific endeavor − one that should ideally be performed for every transcription factor in as many cell types as possible. A major hurdle on the way to this goal is the necessity for a specific, ChIP-grade antibody for each transcription factor of interest, which is often not available. Here, we describe CETCh-seq, a recently published method utilizing genome engineering with the CRISPR/Cas9 system to circumvent the need for a specific antibody. Using the CETCh-seq method, targeted genomic editing results in an epitope-tagged transcription factor, which is recognized by a well-characterized, standard antibody, efficacious for ChIP-seq. We have used CETCh-seq in human cancer cell lines as well as mouse embryonic stem cells. We find that roughly 60% of transcription factors tagged using CETCh-seq produce a high quality ChIP-seq map, a significant improvement over traditional antibody-based methods. Transcription factors binding to precise locations in the human genome controls cell identity. Over 1,800 genes in humans encode transcription factors, yet only a minority have been assayed for where they bind. We describe CETCh-seq, a method combining CRISPR/Cas9 and epitope tagging to assay a large fraction of factors with ChIP-seq.

Beschreibung: Cofactor squelching is the term used to describe competition between transcription factors (TFs) for a limited amount of cofactors in a cell with the functional consequence that TFs in a given cell interfere with the activity of each other. Since cofactor squelching was proposed based primarily on reporter assays some 30 years ago, it has remained controversial, and the idea that it could be a physiologically relevant mechanism for transcriptional repression has not received much support. However, recent genome-wide studies have demonstrated that signal-dependent TFs are very often absent from the enhancers that are acutely repressed by those signals, which is consistent with an indirect mechanism of repression such as squelching. Here we review these recent studies in the light of the classical studies of cofactor squelching, and we discuss how TF cooperativity in so-called hotspots and super-enhancers may sensitize these to cofactor squelching. Cofactor squelching describes the competition between transcription factors (TFs) for a limited amount of cofactors in the cell. Here we review recent genome-wide studies supporting cofactor squelching as a general mechanism of repression and discuss how TF cooperativity in so-called hotspots and super-enhancers may sensitize these to cofactor squelching.

Beschreibung: Interleukin-1 receptor-associated kinase-1 (IRAK1) is linked to the pathogenesis of atherosclerosis; however, its role in macrophage foam cell formation is not known. Therefore, the present study investigated the role of IRAK1 in lipid uptake, biosynthesis, and efflux in THP-1 derived macrophages and human monocyte-derived macrophages (HMDMs). Ox-LDL (40 μg/mL, 15 minutes–48 hours) treatment induced time-dependent increase in IRAK1, IRAK4, and Stat1 activation in THP-1 derived macrophages. IRAK1/4 inhibitor (INH) or IRAK1 siRNA significantly attenuated cholesterol accumulation, DiI-Ox-LDL binding, and uptake while cholesterol efflux to apoAI and HDL was enhanced in THP-1 derived macrophages and HMDMs. Ox-LDL treatment significantly increased the mRNA expression of CD36, LOX-1, SR-A, ABCA1, ABCG1, Caveolin-1, CYP27A1 while that of SR-BI was decreased. IRAK1/4 inhibition or IRAK1 knockdown, however, attenuated Ox-LDL-induced CD36 expression; augmented ABCA1 and ABCG1 expression while expression of others was unaffected in THP-1 derived macrophages and HMDMs. Moreover, IRAK1/4 inhibition had no significant effect on genes involved in lipid biosynthesis. In IRAK1/4 INH pre-treated THP-1 derived macrophages Ox-LDL-induced Stat1 phosphorylation and its binding to CD36 promoter was significantly attenuated while LXRα expression and its binding to the ABCA1/ABCG1 locus, NFATc2 activation and its binding to ABCA1 locus was enhanced. The present study thus demonstrates that IRAK regulates lipid accumulation by modulating CD36-mediated uptake and ABCA1-, ABCG1-dependent cholesterol efflux. Therefore, IRAK1 can be a potential target for preventing macrophage foam cell formation. Ox-LDL induces IRAK activation and foam cell formation. IRAK1 activation positively modulates CD36 expression and cholesterol uptake through Stat1. At the same time IRAK also regulates ABCA1 and ABCG1 expression and cholesterol efflux by modulating transcriptional activity of LXRα and NFATc2.

Beschreibung: Six years ago, the Singer lab published a landmark paper which described how individual mRNA particles cross the nuclear pore complex in mammalian tissue culture cells. This involved the simultaneous imaging of mRNAs, each labeled by a large number of tethered fluorescent proteins and fluorescently tagged nuclear pore components. Now two groups have applied this technique to the budding yeast Saccharomyces cerevisiae . Their results indicate that in the course of nuclear export, mRNAs likely engage complexes that are present on either side of the pore and that these interactions are modulated by proteins present in the messenger ribonucleoprotein (mRNP) complex. These findings lend support to the notion that just before and/or after the completion of nuclear export, mRNPs undergo one or more maturation steps that prepare the packaged mRNAs for translation. These results represent new and exciting insights into the mechanism of mRNA nuclear export. Newly synthesized mRNAs are packaged into large ribonucleoprotein complexes in the nucleus. During nuclear export, these complexes dock to the nuclear pore and their composition is altered. Recently, two groups have imaged individual mRNA export events in Saccharomyces cerevisiae in order to dissect the molecular machinery that mediates docking.

Beschreibung: Few topics have intrigued biologists as much as the evolution of sex. Understanding why sex persists despite its costs requires not just rigorous theoretical study, but also empirical data on related fundamental issues, including the nature of genetic variance for fitness, patterns of genetic interactions, and the dynamics of adaptation. The increasing feasibility of examining genomes in an experimental context is now shedding new light on these problems. Using this approach, McDonald et al. recently demonstrated that sex uncouples beneficial and deleterious mutations, allowing selection to proceed more effectively with sex than without. Here we discuss the insights provided by this study, along with other recent empirical work, in the context of the major theoretical models for the evolution of sex. Competing hypotheses for the evolutionary benefits of sex are increasingly amenable to empirical testing, thanks to advances in genomics. Recent experiments suggest that sex increases genetic variance by uncoupling beneficial alleles from deleterious alleles in the same genome, allowing selection to be more effective and increasing long-term mean fitness.

Beschreibung: Mature spermatozoa are permeable to foreign DNA and RNA molecules. Here I propose a model, whereby extrachromosomal genetic information, mostly encoded in the form of RNA in somatic cells, can cross the Weismann barrier and reach epididymal spermatozoa. LINE-1 retrotransposon-derived reverse transcriptase (RT) can play key roles in the process by expanding the RNA-encoded information. Retrotransposon-encoded RT is stored in mature gametes, is highly expressed in early embryos and undifferentiated cells, and becomes downregulated in differentiated cells. In turn, RT plays a role in developmental control, as its inhibition arrests developmental progression of early embryos with globally altered transcriptomic profiles. Thus, sperm cells act as recipients, and transgenerational vectors of somatically derived genetic information which they pass to the next generation with the potential to modify the fate of the developing embryos. Non-Mendelian transgenerational inheritance is a growingly recognized phenomenon, yet elusive in molecular terms. I propose that RNA-based information released from somatic cells can cross the Weismann barrier, be internalized in epididymal spermatozoa which mediate the acquisition of new traits in the embryos at fertilization. Sperm endogenous reverse transcriptase plays key roles in the process.

Beschreibung: Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases. There are a number of intermediate phenotypes or endophenotypes that contribute to the pathogenesis of complex diseases. The identification of genetic determinants that contribute to the variability of these intermediate phenotypes can be a global strategy to identify part of the missing heritability of complex diseases.

Beschreibung: “Antibiotic resistance is usually associated with a fitness cost” is frequently accepted as common knowledge in the field of infectious diseases. However, with the advances in high-throughput DNA sequencing that allows for a comprehensive analysis of bacterial pathogenesis at the genome scale, including antibiotic resistance genes, it appears that this paradigm might not be as solid as previously thought. Recent studies indicate that antibiotic resistance is able to enhance bacterial fitness in vivo with a concomitant increase in virulence during infections. As a consequence, strategies to minimize antibiotic resistance turn out to be not as simple as initially believed. Indeed, decreased antibiotic use may not be sufficient to let susceptible strains outcompete the resistant ones. Here, we put in perspective these findings and review alternative approaches, such as preventive and therapeutic anti-bacterial immunotherapies that have the potential to by-pass the classic antibiotics. Antibiotic resistance is able to enhance bacterial fitness in vivo as well as bacterial virulence during infections. Cutting back on antibiotic use may not be sufficient to let susceptible strains outcompete the resistant ones. Alternative approaches that have the potential to by-pass the classic antibiotics have to be considered.

Beschreibung: In the field of germline development in amniote vertebrates, primordial germ cell (PGC) specification in birds and reptiles remains controversial. Avians are believed to adopt a predetermination or maternal specification mode of PGC formation, contrary to an inductive mode employed by mammals and, supposedly, reptiles. Here, we revisit and review some key aspects of PGC development that channelled the current subdivision, and challenge the position of birds and reptiles as well as the ‘binary’ evolutionary model of PGC development in vertebrates. We propose an alternative view on PGC specification where germ plasm plays a role in laying the foundation for the formation of PGC precursors (pPGC), but not necessarily of PGCs. Moreover, inductive mechanisms may be necessary for the transition from pPGCs to PGCs. Within this framework, the implementation of data from birds and reptiles could provide new insights on the evolution of PGC specification in amniotes. PGC specification is currently believed to occur according to two modalities, maternal specification or induction. We propose an alternative view whereby maternal determinants (germ plasm), when present, guide specification of (multipotent) PGC precursors (pPGCs), but induction is needed for the transition from pPGCs to PGCs in amniotes, and perhaps all animals (The existence of germ line stem cells is sex and/or species dependent).

Beschreibung: Bacterial populations are heterogeneous, which in many cases can provide a selective advantage during changes in environmental conditions. In some instances, heterogeneity exists at the genetic level, in which significant allelic variation occurs within a population seeded by a single cell. In other cases, heterogeneity exists due to phenotypic differences within a clonal, genetically identical population. A variety of mechanisms can drive this latter strategy. Stochastic fluctuations can drive differential gene expression, but heterogeneity in gene expression can also be driven by environmental changes sensed by individual cells residing in distinct locales. Utilizing multiple single cell approaches, workers have started to uncover the extent of heterogeneity within bacterial populations. This review will first describe several examples of phenotypic and genetic heterogeneity, and then discuss many single cell approaches that have recently been applied to define heterogeneity within bacterial populations. Individual cells within replicating bacterial populations express distinct phenotypes, which can develop when individuals encounter small microenvironments and respond to environmental cues, and can also exist prior to an environmental change. The extent of microbial heterogeneity can now be probed at the single cell level due to recent technological advances.

Beschreibung: The germ track is the cellular path by which genes are transmitted to future generations whereas somatic cells die with their body and do not leave direct descendants. Transposable elements (TEs) evolve to be silent in somatic cells but active in the germ track. Thus, the performance of most bodily functions by a sequestered soma reduces organismal costs of TEs. Flexible forms of gene regulation are permissible in the soma because of the self-imposed silence of TEs, but strict licensing of transcription and translation is maintained in the germ track to control proliferation of TEs. Delayed zygotic genome activation (ZGA) and maternally inherited germ granules are adaptations that enhance germ-track security. Mammalian embryos exhibit very early ZGA associated with extensive mobilization of retroelements. This window of vulnerability to retrotransposition in early embryos is an indirect consequence of evolutionary conflicts within the mammalian genome over postzygotic maternal provisioning. The germ track is the cellular lineage of germ cells. It has two segments: a pluripotent germ-stem that has somatic cells as well as germ cells as descendants and a dedicated germline. Transposable elements benefit from transposition in the germ track but not from transposition in the soma.

Beschreibung: Recently, we found that the Pseudomonas aeruginosa type II secreted protease IV functions as a unique Arabidopsis innate immunity elicitor. The protease IV-activated pathway involves G protein signaling and raises the question of how protease elicitation leads to the activation of G protein-mediated signaling, because plants do not appear to have metazoan-like G protein-coupled receptors. Importantly, our data suggest that Arabidopsis has evolved a mechanism to detect the proteolytic activity of a pathogen-encoded protease, supporting the host-pathogen arms race model. In the case of opportunistic multi-host pathogens like P. aeruginosa , however, it is not plausible that P. aeruginosa is simultaneously co-evolving in a gene-for-gene manner with all of its potential hosts, which include plants, nematodes, insects, and mammals. This prompts us to ask what is the driving force for co-evolution of defense response in Arabidopsis and pathogenesis of P. aeruginosa , which might not have been subject to iterative cycles of evolutionary selections. Pseudomonas aeruginosa type II-secreted protease IV elicits an immune response in Arabidopsis through a novel signaling pathway that involves the heterotrimeric G protein complex and a scaffolding protein for mitogen-activated protein kinase cascade. Intriguingly, the sensory complex and the mechanisms by which it mediates the protease IV response remain elusive.

Beschreibung: Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co-activators, co-repressors, multiple TFs, histone-modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a pioneering role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP-Seq, digital genomic footprinting, DHS-Seq, live cell protein dynamics, and biochemical studies of ATP-dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy-dependent, non-equilibrium steady states. During dynamic assisted loading (DynALoad), an initiator factor recruits ATP-dependent chromatin remodeler complexes to open closed chromatin regions and assists the binding of a second transcription factor. Contrary to the pioneer factor model, any transcription factor can potentially initiate this process or function as the assisted protein.

Beschreibung: The spread of exotic species represents a major driver of biological change across the planet. While dispersal and colonization are natural biological processes, we suggest that the failure to recognize increasing rates of human-facilitated self-introductions may represent a threat to native lineages. Notably, recent biogeographic analyses have revealed numerous cases of biological range shifts in response to anthropogenic impacts and climate change. In particular, ancient DNA analyses have revealed several cases in which lineages traditionally thought to be long-established “natives” are in fact recent colonizers. Such range expansion events have apparently occurred in response to human-mediated native biodiversity declines and ecosystem change, particularly in recently colonized, isolated ecosystems such as New Zealand. While such events can potentially boost local biodiversity, the spread of exotic lineages may also hasten the decline of indigenous species, so it is essential that conservation managers recognize these rapid biotic shifts.​ Ancient DNA analyses have revealed several cases of self-introductions of exotic species in response to human-mediated native biodiversity declines and ecosystem change. We discuss the potential impacts of self-introduced lineages on indigenous biota, and argue that it is essential that conservation managers recognize and respond to these rapid biotic shifts.

Beschreibung: We hypothesize that under the predicted scenario of climate change epigenetically mediated environmental sex determination could become an epigenetic trap. Epigenetically regulated environmental sex determination is a mechanism by which species can modulate their breeding strategies to accommodate environmental change. Growing evidence suggests that epigenetic mechanisms may play a key role in phenotypic plasticity and in the rapid adaptation of species to environmental change, through the capacity of organisms to maintain a non-genetic plastic memory of the environmental and ecological conditions experienced by their parents. However, inherited epigenetic variation could also be maladaptive, becoming an epigenetic trap. This is because environmental sex determination can alter sex ratios by increasing the survival of one of the sexes at the expense of negative fitness consequences for the other, which could lead not only to the collapse of natural populations, but also have an impact in farmed animal and plant species. Methylome by environment interactions can regulate sex determination helping species to rapidly adapt to changing environments. However, under the predicted global warming conditions this adaptive strategy could become an epigenetic trap by creating extreme imbalances in sex ratios, which could affect both natural populations and farmed animal and plant species.

Beschreibung: A 365 million year-old trilobite moult-carcass assemblage was described by Błażejowski et al. (2015) as the oldest direct evidence of moulting in the arthropod fossil record. Unfortunately, their suppositions are insufficiently supported by the data provided. Instead, the morphology, configuration and preservational context of the highly fossiliferous locality (Kowala Quarry, Poland) suggest that the specimen consists of two overlapping, queued carcasses. The wider fossil record of moulting actually extends back 520 million years, providing an unparalleled opportunity to study behaviour, ecology and development in early animals. Taking cues from modern analogues, it is possible to quantify precise details about moulting behaviour to determine broad-scale evolutionary trends, ontogenetic sequences and morphological selection pressures. In this review, we argue that this rich source of data has been underused in evolutionary studies, though has great potential for investigating the life history and evolution of arthropods in deep time. Exoskeleton moulting occurs in arthropods during growth, and Błażejowski et al. (2015) described putative moulting in a 365 million year-old trilobite. We argue this specimen is not a moult assemblage, but show that reliable studies on trilobite moulting reveal evolutionary trends in behaviour, ecology and development in deep time.

Beschreibung: Mutations in enhancer-associated chromatin-modifying components and genomic alterations in non-coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin-modifying factors might affect enhancer activity of disease-relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer-regulated and disease-relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. Enhancer deregulation underlies various diseases. It can be caused by mutations in enhancer-associated chromatin-modifying factors such as UTX/KDM6A, MLL3/KMT2C, and MLL4/KMT2D or alternatively by mutations or genomic alterations of disease, or cancer gene enhancers. Both cases result in altered enhancer activity of disease-relevant genes such as tumor suppressor or oncogenes.

Beschreibung: The recent availability of multiple avian genomes has laid the foundation for a huge variety of comparative genomics analyses including scans for changes and signatures of selection that arose from adaptions to new ecological niches. Nocturnal adaptation in birds, unlike in mammals, is comparatively recent, a fact that makes birds good candidates for identifying early genetic changes that support adaptation to dim-light environments. In this review, we give examples of comparative genomics analyses that could shed light on mechanisms of adaptation to nocturnality. We present advantages and disadvantages of both “data-driven” and “hypothesis-driven” approaches that lead to the discovery of candidate genes and genetic changes promoting nocturnality. We anticipate that the accessibility of multiple genomes from the Genome 10K Project will allow a better understanding of evolutionary mechanisms and adaptation in general. Comparative genomics is an exciting field that can pinpoint differences in genomic regions, which occur as a result of an environmental change. The future availability of multiple bird genomes opens an unprecedented era for research of mechanisms of nocturnal adaptation.

Beschreibung: Skeletal muscle stem cells or satellite cells are responsible for muscle regeneration in the adult. Although satellite cells are highly resistant to stress, and display greater capacity to repair molecular damage than the committed progeny, their regenerative potential declines with age. During ageing, satellite cells switch to a state of permanent cell cycle arrest or senescence which prevents their activation. A recent study reveals that the senescence of satellite cell relies on defective autophagy, the quality control mechanism that degrades damaged proteins and organelles. Molecular damage is generated by oxidative stress that also promotes epigenetic changes that activate the expression of master genes, in a double-hit mechanism that ensures senescence. Importantly, genetic, and pharmacological correction of defective autophagy reverses satellite cell senescence and restores muscle regeneration in geriatric mice, with perspectives of modulating age-related functional decline of muscle. This study provides new clues to understand stem cell and organismal ageing. The activation and regeneration decline of muscle stem (satellite) cells with age becomes dramatic in very old (geriatric) mice, whose satellite cells enter an irreversible senescent state. This impairment can be reversed by restoring protein and organelle turnover through autophagy and by reducing oxidative stress, which also prevents epigenetic modifications.

Beschreibung: X chromosome inactivation (XCI) is an essential epigenetic process that ensures X-linked gene dosage equilibrium between sexes in mammals. XCI is dynamically regulated during development in a manner that is intimately linked to differentiation. Numerous studies, which we review here, have explored the dynamics of X inactivation and reactivation in the context of development, differentiation and diseases, and the phenotypic and molecular link between the inactive status, and the cellular context. Here, we also assess whether XCI is a uniform mechanism in mammals by analyzing epigenetic signatures of the inactive X (Xi) in different species and cellular contexts. It appears that the timing of XCI and the epigenetic signature of the inactive X greatly vary between species. Surprisingly, even within a given species, various Xi configurations are found across cellular states. We discuss possible mechanisms underlying these variations, and how they might influence the fate of the Xi. X chromosome inactivation initiates during early mammalian development in a manner that correlates with cellular differentiation, and the mechanisms coupling these processes are starting to be unraveled. Once established, the inactive status is stably transmitted throughout cell divisions. Recent data highlight, however, variation in Xi features, both within and across species.

Beschreibung: The largest proportion of microRNAs in humans (ca. 40–50%) originated in the phylogenetic grouping defined as primates. The dynamic evolution of this family of non-coding RNA is further demonstrated by the presence of microRNA unique to the human species. Investigations into the role of microRNA in cancer have until recently mainly focused on the more ancient members of this RNA family that are widely conserved in the animal kingdom. As I describe in this review the evolutionary young lineage and species-specific microRNA could be important contributors to cancers, especially in particular organs in primates compared to more distantly-related research models. Elucidating the biological significance of primate and human-specific microRNA in cancer could have important implications for cancer research and the use of non-primate animal models. The human miRNAome can be divided into miRNAs that are widely conserved, those that are primate-specific, and those that are human-specific. The latter two categories can also contribute to tumor development and complicate the study of human cancers in non-primate animal models.

Beschreibung: This recent meeting covered non-bilaterian (e.g., cnidarians, ctenophores, and sponges) animals broadly, but with emphasis in four areas: 1) New genomic resources and tools for functional studies, 2) advances in developmental and regeneration studies, 3) the evolution and function of nervous systems, 4) symbiosis and the holobiome.