ALBERT

Description: Flowering time is one of the key determinants of crop adaptation to local environments during domestication. However, the genetic basis underlying flowering time is yet to be elucidated in most cereals. Although staple cereals, such as rice, maize, wheat, barley, and sorghum, have spread and adapted to a wide range of ecological environments during domestication, it is yet to be determined whether they have a common genetic basis for flowering time. In this study, we show, through map-based cloning, that flowering time in sorghum is controlled by a major quantitative trait locus (QTL) Heading Date 1 ( HD1 ), located on chromosome 10. The causal gene encodes the CONSTANS gene family which contains a CCT domain. A 5-bp deletion of a minor allele present in the coding sequence leads to a gene frameshift that delays flowering in sorghum. In contrast, in foxtail millet, association mapping of HD1 showed a common causal site with a splicing variant from "GT" to "AT" that was highly correlated with flowering time. In addition, the rice HD1 gene is known to harbor several causal variants controlling flowering time. These data indicate that the major flowering time QTL HD1 was under parallel domestication in sorghum, foxtail millet, and rice. The pattern of common mixed minor, or even rare, causal alleles in HD1 across different species may be representative of the genetic basis of the domestication syndrome. Furthermore, large DNA sequence analysis of HD1 revealed multiple origins for domesticated sorghum and a single origin for domesticated foxtail millet.

Description: Aims When sympatric flowering plant species in a natural community share pollinators, study of plant–plant interactions via interspecific pollen transfer (IPT) is essential for understanding species coexistence. However, little is known about the extent of IPT between interactive species and its causes. Methods To explore how sympatric flowering plants sharing pollinators minimize deleterious effects of IPT, we investigated the pollination ecology of two endemic species, Salvia przewalskii and Delphinium yuanum , in an alpine meadow in the Hengduan Mountains, southwest China. We quantified conspecific and interspecific visits by shared bumblebee pollinators, amounts of pollen placed on different body sites of the pollinators and stigmatic pollen loads on open-pollinated flowers. To examine whether IPT affects female fitness, we measured pollen germination and seed production in the two species in an artificial pollination experiment. Important Findings One bumblebee species, Bombus trifasciatus , was found to be the sole effective pollinator for the two coflowering species. Pollination experiments indicated that deposition of heterospecific pollen could significantly decrease seed set in both species. Experiments showed that S. przewalskii pollen could germinate well on stigmas of D. yuanum , inhibiting conspecific pollen germination in D. yuanum . However, seed set was not lower under open pollination than under cross-pollination within species, suggesting that no female fitness loss was caused by IPT. In foraging bouts with pollinator switches, switches from S. przewalskii to D. yuanum were relatively more frequent (8.27%) than the converse (1.72%). However, IPT from S. przewalskii to D. yuanum accounted for only 1.82% of total stigmatic pollen loads while the reverse IPT to S. przewalskii was 8.70%, indicating that more switches of bumblebees to D. yuanum did not result in higher IPT. By contrast, selection for reduced IPT to S. przewalskii would limit pollinator switches from D. yuanum . We found that a bumblebee generally carried pollen grains from both species but the two species differed in the position of pollen placement on the bumblebee’s body; S. przewalskii ’ s pollen was concentrated on the dorsal thorax while D. yuanum ’ s pollen was concentrated ventrally on the head. This differential pollen placement along with pollinator fidelity largely reduced IPT between the two species with a shared pollinator.

Description: Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G〉T, p.191Gly〉Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G〉A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G〉A mutation, or both m.11778G〉A and heterozygous p.191Gly〉Val mutations and symptomatic subjects harboring m.11778G〉A and homozygous p.191Gly〉Val mutations) and controls lacking these mutations. The 191Gly〉Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA Tyr were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly〉Val and m.11778G〉A mutations. The failure in tRNA Tyr metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly〉Val and m.11778G〉A mutations. The YARS2 p.191Gly〉Val mutation worsened the respiratory phenotypes associated with m.11778G〉A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G〉A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2 .

Description: Messenger RNA (mRNA) secondary structure decreases the elongation rate, as ribosomes must unwind every structure they encounter during translation. Therefore, the strength of mRNA secondary structure is assumed to be reduced in highly translated mRNAs. However, previous studies in vitro reported a positive correlation between mRNA folding strength and protein abundance. The counterintuitive finding suggests that mRNA secondary structure affects translation efficiency in an undetermined manner. Here, we analyzed the folding behavior of mRNA during translation and its effect on translation efficiency. We simulated translation process based on a novel computational model, taking into account the interactions among ribosomes, codon usage and mRNA secondary structures. We showed that mRNA secondary structure shortens ribosomal distance through the dynamics of folding strength. Notably, when adjacent ribosomes are close, mRNA secondary structures between them disappear, and codon usage determines the elongation rate. More importantly, our results showed that the combined effect of mRNA secondary structure and codon usage in highly translated mRNAs causes a short ribosomal distance in structural regions, which in turn eliminates the structures during translation, leading to a high elongation rate. Together, these findings reveal how the dynamics of mRNA secondary structure coupling with codon usage affect translation efficiency.

Description: The use of multiple replication origins in archaea is not well understood. In particular, little is known about their specific control mechanisms. Here, we investigated the active replication origins in the three replicons of a halophilic archaeon, Haloarcula hispanica , by extensive gene deletion, DNA mutation and genome-wide marker frequency analyses. We revealed that individual origins are specifically dependent on their co-located cdc6 genes, and a single active origin/ cdc6 pairing is essential and sufficient for each replicon. Notably, we demonstrated that the activities of oriC1 and oriC2 , the two origins on the main chromosome, are differently controlled. A G-rich inverted repeat located in the internal region between the two inverted origin recognition boxes (ORBs) plays as an enhancer for oriC1 , whereas the replication initiation at oriC2 is negatively regulated by an ORB-rich region located downstream of oriC2-cdc6E , likely via Cdc6E-titrating. The oriC2 placed on a plasmid is incompatible with the wild-type (but not the oriC2 ) host strain, further indicating that strict control of the oriC2 activity is important for the cell. This is the first report revealing diverse control mechanisms of origins in haloarchaea, which has provided novel insights into the use and coordination of multiple replication origins in the domain of Archaea.

Description: Gene expression is modulated by multiple mechanisms, including genetic and/or epigenetic regulation, and associated with the processes of cellular differentiation and morphogenesis. Single nucleotide polymorphisms (SNPs) and DNA methylation play important roles in regulating gene expression. In this study, we focused on revealing the relationship between SNPs, DNA methylation and gene expression in two human populations genome-wide through proposing four regulation patterns and developed maximum likelihood estimate models. Using simulated data with different correlation coefficients between any two traits, the power of our approach showed a favourable performance and relative stability. In all, 6733 SNP–CpG-gene pairs including 957 genes were obtained in Northern European ancestry (CEU) population. As the results showed, SNPs and DNA methylation had approximately the same effect on expression regulation of 49% genes, which was termed cooperative/antagonistic regulation pattern. Less than 30% of genes are controlled only by one of the factors (SNP/DNA methylation). The others showed SNPs that affect methylation have no consequent effects or crosstalk regulation on gene expression. Similar result was shown in Yourba (YRI) population. Specific genes were inferred using the different mechanisms of gene regulation involved in complex diseases by combining literature. This approach provides a method to comprehensively assess regulation patterns of gene expression in the whole genome.

Description: Epithelial-to-mesenchymal transition (EMT) is a complex multistep process in which phenotype switches are mediated by a network of transcription factors (TFs). Systematic characterization of all dynamic TFs controlling EMT state transitions, especially for the intermediate partial-EMT state, represents a highly relevant yet largely unexplored task. Here, we performed a computational analysis that integrated time-course EMT transcriptomic data with public cistromic data and identified three synergistic master TFs (ETS2, HNF4A and JUNB) that regulate the transition through the partial-EMT state. Overexpression of these regulators predicted a poor clinical outcome, and their elimination readily abolished TGF-β-induced EMT. Importantly, these factors utilized a clique motif, physically interact and their cumulative binding generally characterized EMT-associated genes. Furthermore, analyses of H3K27ac ChIP-seq data revealed that ETS2, HNF4A and JUNB are associated with super-enhancers and the administration of BRD4 inhibitor readily abolished TGF-β-induced EMT. These findings have implications for systematic discovery of master EMT regulators and super-enhancers as novel targets for controlling metastasis.

Description: We present investigations of the feedback of a luminous Herbig Be star, IL Cep. We mapped the vicinity of IL Cep in the J = 1-0 transitions of 12 CO, 13 CO and C 18 O molecular lines with the Purple Mountain Observatory 13.7 m telescope. Archival data from Wide-field Infrared Survey Explorer were also employed. A parsec-scale cavity that has probably been excavated by the dominant HBe star, IL Cep, is revealed. An expanding shell-like structure featured by 12 CO(J = 1-0) emission was found surrounding the cavity, which embeds several 13 CO(J = 1-0) molecular clumps. The density and velocity gradients imply strong stellar winds from exciting stars, this is consistent with the morphology of molecular cloud. The 12 CO(J = 1-0) spectra show broad blue wings with a width of about 3.5 km s –1 . We suggest that the broad blue wings could be emission from the molecular gas shocked by stellar winds, while the main narrow component may originate from pre-shocked gas. Several bright bow-shaped rims have been detected at 12 μm, which serve as the interface of the molecular cloud facing UV dissipation from the exciting stars. The rims all have an orientation facing IL Cep, this may indicate the pre-dominant effects of IL Cep on its surroundings. A very young star candidate (about 10 4.8  yr) was found in the head of one bright rim, but its triggered origin is uncertain. All results achieved in this paper suggest that IL Cep has violent effects on its surroundings.

Description: DNA methylation is a key epigenetic mark that is critical for gene regulation in multicellular eukaryotes. Although various human cell types may have the same genome, these cells have different methylomes. The systematic identification and characterization of methylation marks across cell types are crucial to understand the complex regulatory network for cell fate determination. In this study, we proposed an entropy-based framework termed SMART to integrate the whole genome bisulfite sequencing methylomes across 42 human tissues/cells and identified 757 887 genome segments. Nearly 75% of the segments showed uniform methylation across all cell types. From the remaining 25% of the segments, we identified cell type-specific hypo/hypermethylation marks that were specifically hypo/hypermethylated in a minority of cell types using a statistical approach and presented an atlas of the human methylation marks. Further analysis revealed that the cell type-specific hypomethylation marks were enriched through H3K27ac and transcription factor binding sites in cell type-specific manner. In particular, we observed that the cell type-specific hypomethylation marks are associated with the cell type-specific super-enhancers that drive the expression of cell identity genes. This framework provides a complementary, functional annotation of the human genome and helps to elucidate the critical features and functions of cell type-specific hypomethylation.

Description: Motivation: In mammalian cells, many genes are silenced by genome methylation. DNA methyltransferases and polycomb repressive complexes, which both lack sequence-specific DNA-binding motifs, are recruited by long non-coding RNA (lncRNA) to specific genomic sites to methylate DNA and chromatin. Increasing evidence indicates that many lncRNAs contain DNA-binding motifs that can bind to DNA by forming RNA:DNA triplexes. The identification of lncRNA DNA-binding motifs and binding sites is essential for deciphering lncRNA functions and correct and erroneous genome methylation; however, such identification is challenging because lncRNAs may contain thousands of nucleotides. No computational analysis of typical lncRNAs has been reported. Here, we report a computational method and program ( LongTarget ) to predict lncRNA DNA-binding motifs and binding sites. We used this program to analyse multiple antisense lncRNAs, including those that control well-known imprinting clusters, and obtained results agreeing with experimental observations and epigenetic marks. These results suggest that it is feasible to predict many lncRNA DNA-binding motifs and binding sites genome-wide. Availability and implementation: Website of LongTarget : lncrna.smu.edu.cn , or contact: hao.zhu@ymail.com . Contact: zhuhao@smu.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online.