ALBERT

Description: Mammalian ncRNA-disease repository: a global view of ncRNA-mediated disease network Cell Death and Disease 4, e765 (August 2013). doi:10.1038/cddis.2013.292 Authors: Y Wang, L Chen, B Chen, X Li, J Kang, K Fan, Y Hu, J Xu, L Yi, J Yang, Y Huang, L Cheng, Y Li, C Wang, K Li, X Li, J Xu & D Wang

Description: Motivation: Alzheimer’s disease (AD) is a severe neurodegenerative disease of the central nervous system that may be caused by perturbation of regulatory pathways rather than the dysfunction of a single gene. However, the pathology of AD has yet to be fully elucidated. Results: In this study, we systematically analyzed AD-related mRNA and miRNA expression profiles as well as curated transcription factor (TF) and miRNA regulation to identify active TF and miRNA regulatory pathways in AD. By mapping differentially expressed genes and miRNAs to the curated TF and miRNA regulatory network as active seed nodes, we obtained a potential active subnetwork in AD. Next, by using the breadth-first-search technique, potential active regulatory pathways, which are the regulatory cascade of TFs, miRNAs and their target genes, were identified. Finally, based on the known AD-related genes and miRNAs, the hypergeometric test was used to identify active pathways in AD. As a result, nine pathways were found to be significantly activated in AD. A comprehensive literature review revealed that eight out of nine genes and miRNAs in these active pathways were associated with AD. In addition, we inferred that the pathway hsa-miR-146a-〉STAT1-〉MYC, which is the source of all nine significantly active pathways, may play an important role in AD progression, which should be further validated by biological experiments. Thus, this study provides an effective approach to finding active TF and miRNA regulatory pathways in AD and can be easily applied to other complex diseases. Contact: lixia@hrbmu.edu.cn or lw2247@gmail.com . Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Endometriosis is a complex and enigmatic disease that arises from the interplay among multiple genetic and environmental factors. The defining feature of endometriosis is the deposition and growth of endometrial tissues at sites outside of the uterine cavity. Studies to date have established that endometriosis is heritable but have not addressed the causal genetic variants for this disease. Here, we conducted whole-exome sequencing to comprehensively search for somatic mutations in both eutopic and ectopic endometrium from 16 endometriosis patients and five normal control patients using laser capture microdissection. We compared the mutational landscape of ectopic endometrium with the corresponding eutopic sample from endometriosis patients compared with endometrium from normal women and identified previously unreported mutated genes and pathway alternations. Statistical analysis of exome data identified that most genes were specifically mutated in both eutopic and ectopic endometrium cells. In particular, genes that are involved in biological adhesion, cell–cell junctions, and chromatin-remodeling complex(es) were identified, which partially supports the retrograde menstruation theory that proposes that endometrial cells are refluxed through the fallopian tubes during menstruation and implanted onto the peritoneum or pelvic organs. Conspicuously, when we compared exomic mutation data for paired eutopic and ectopic endometrium, we identified a mutational signature in both endometrial types for which no overlap in somatic single nucleotide variants were observed. These mutations occurred in a mutually exclusive manner, likely because of the discrepancy in endometriosis pathology and physiology, as eutopic endometrium rapidly regrows, and ectopic endometrial growth is inert. Our findings provide, to our knowledge, an unbiased view of the landscape of genetic alterations in endometriosis and vital information for indicating that genetic alterations in cytoskeletal and chromatin-remodeling proteins could be involved in the pathogenesis of endometriosis, thus implicating a novel therapeutic possibility for endometriosis.

Description: Despite growing consensus that long intergenic non-coding ribonucleic acids (lincRNAs) are modulators of cancer, the knowledge about the deoxyribonucleic acid (DNA) methylation patterns of lincRNAs in cancers remains limited. In this study, we constructed DNA methylation profiles for 4629 tumors and 705 normal tissue samples from 20 different types of human cancer by reannotating data of DNA methylation arrays. We found that lincRNAs had different promoter methylation patterns in cancers. We classified 2461 lincRNAs into two categories and three subcategories, according to their promoter methylation patterns in tumors. LincRNAs with resistant methylation patterns in tumors had conserved transcriptional regulation regions and were ubiquitously expressed across normal tissues. By integrating cancer subtype data and patient clinical information, we identified lincRNAs with promoter methylation patterns that were associated with cancer status, subtype or prognosis for several cancers. Network analysis of aberrantly methylated lincRNAs in cancers showed that lincRNAs with aberrant methylation patterns might be involved in cancer development and progression. The methylated and demethylated lincRNAs identified in this study provide novel insights for developing cancer biomarkers and potential therapeutic targets.

Description: PIAS1-modulated Smad2/4 complex activation is involved in zinc-induced cancer cell apoptosis Cell Death and Disease 4, e811 (September 2013). doi:10.1038/cddis.2013.333 Authors: N Yang, B Zhao, A Rasul, H Qin, J Li & X Li

Description: Author(s): W. K. Yeoh, B. Gault, X. Y. Cui, C. Zhu, M. P. Moody, L. Li, R. K. Zheng, W. X Li, X. L. Wang, S. X. Dou, G. L. Sun, C. T. Lin, and S. P. Ringer Local fluctuations in the distribution of dopant atoms are thought to cause the nanoscale electronic disorder or phase separation in pnictide superconductors. Atom probe tomography has enabled the first direct observations of dopant species clustering in a K-doped 122-phase pnictide. First-principle... [Phys. Rev. Lett. 106, 247002] Published Wed Jun 15, 2011

Description: Phosphoinositides serve as address labels for recruiting peripheral cytoplasmic proteins to specific subcellular compartments, and as endogenous factors for modulating the activity of integral membrane proteins. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a plasma-membrane (PM)–specific phosphoinositide and a positive cofactor required for the activity of most PM channels and transporters. This requirement for phosphoinositide cofactors has been proposed to prevent PM channel/transporter activity during passage through the biosynthetic/secretory and endocytic pathways. To determine whether intracellularly localized channels are similarly “inactivated” at the PM, we studied PIP2 modulation of intracellular TRPML1 channels. TRPML1 channels are primarily localized in lysosomes, but can also be detected temporarily in the PM upon lysosomal exocytosis. By directly patch-clamping isolated lysosomes, we previously found that lysosomal, but not PM-localized, TRPML1 is active with PI(3,5)P2, a lysosome-specific PIP2, as the underlying positive cofactor. Here we found that “silent” PM-localized TRPML1 could be activated by depleting PI(4,5)P2 levels and/or by adding PI(3,5)P2 to inside-out membrane patches. Unlike PM channels, surface-expressed TRPML1 underwent a unique and characteristic run-up upon patch excision, and was potently inhibited by a low micromolar concentration of PI(4,5)P2. Conversely, depletion of PI(4,5)P2 by either depolarization-induced activation or chemically induced translocation of 5′-phosphatase potentiated whole-cell TRPML1 currents. PI(3,5)P2 activation and PI(4,5)P2 inhibition of TRPML1 were mediated by distinct basic amino acid residues in a common PIP2-interacting domain. Thus, PI(4,5)P2 may serve as a negative cofactor for intracellular channels such as TRPML1. Based on these results, we propose that phosphoinositide regulation sets compartment-specific activity codes for membrane channels and transporters.

Description: Based on published pollen data from 44 sites in the Loess Plateau and surrounding areas, we recalculate values of Picea abundance digitized from the original diagrams and construct six isopoll maps to reconstruct the distribution of spruce forest at 2000 yr intervals during the Holocene. Spruce forest gradually expanded from about 10 ka BP ago and reached its peak distribution around 8 ka BP. It retained its maximum extent between 8 ka BP and 6 ka BP, broadly covering the subalpine area and stretching to the valleys of the western Loess Plateau with high densities and even reaching the edges of the adjacent desert regions. After 6 ka BP, spruce forest began to retreat to higher elevations. This trend was accelerated after 4 ka BP. After 2 ka BP, it disappeared completely from the Loess Plateau and most of its surrounding areas. Precipitation strongly dominated by the Asian summer monsoon was the primary controlling factor in the distribution of spruce before 2 ka BP. After about 2 ka BP, the increasing intensity of human activity became the primary factor in the disappearance of spruce in the Loess Plateau, resulting in an enormous impact on the present landscape.

Description: Disruption of the nucleotide excision repair (NER) pathway by mutations can cause xeroderma pigmentosum, a syndrome predisposing affected individuals to development of skin cancer. The xeroderma pigmentosum C (XPC) protein is essential for initiating global genome NER by recognizing the DNA lesion and recruiting downstream factors. Here we show that inhibition of the deacetylase and longevity factor SIRT1 impairs global genome NER through suppressing the transcription of XPC in a SIRT1 deacetylase-dependent manner. SIRT1 enhances XPC expression by reducing AKT-dependent nuclear localization of the transcription repressor of XPC. Finally, we show that SIRT1 levels are significantly reduced in human skin tumors from Caucasian patients, a population at highest risk. These findings suggest that SIRT1 acts as a tumor suppressor through its role in DNA repair.