%0 Journal Article %J Nat Commun %D 2014 %T Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3'-UTR landscape across seven tumour types. %A Xia, Zheng %A Donehower, Lawrence A %A Cooper, Thomas A %A Neilson, Joel R %A Wheeler, David A %A Wagner, Eric J %A Li, Wei %K 3' Untranslated Regions %K Cleavage Stimulation Factor %K Gene Expression Regulation, Neoplastic %K Humans %K Neoplasms %K Polyadenylation %K RNA, Messenger %K RNA-Binding Proteins %K Sequence Analysis, RNA %X

Alternative polyadenylation (APA) is a pervasive mechanism in the regulation of most human genes, and its implication in diseases including cancer is only beginning to be appreciated. Since conventional APA profiling has not been widely adopted, global cancer APA studies are very limited. Here we develop a novel bioinformatics algorithm (DaPars) for the de novo identification of dynamic APAs from standard RNA-seq. When applied to 358 TCGA Pan-Cancer tumour/normal pairs across seven tumour types, DaPars reveals 1,346 genes with recurrent and tumour-specific APAs. Most APA genes (91%) have shorter 3'-untranslated regions (3' UTRs) in tumours that can avoid microRNA-mediated repression, including glutaminase (GLS), a key metabolic enzyme for tumour proliferation. Interestingly, selected APA events add strong prognostic power beyond common clinical and molecular variables, suggesting their potential as novel prognostic biomarkers. Finally, our results implicate CstF64, an essential polyadenylation factor, as a master regulator of 3'-UTR shortening across multiple tumour types.

%B Nat Commun %V 5 %P 5274 %8 2014 Nov 20 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/25409906?dopt=Abstract %R 10.1038/ncomms6274 %0 Journal Article %J Cell Stem Cell %D 2014 %T Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. %A Sun, Deqiang %A Luo, Min %A Jeong, Mira %A Rodriguez, Benjamin %A Xia, Zheng %A Hannah, Rebecca %A Wang, Hui %A Le, Thuc %A Faull, Kym F %A Chen, Rui %A Gu, Hongcang %A Bock, Christoph %A Meissner, Alexander %A Göttgens, Berthold %A Darlington, Gretchen J %A Li, Wei %A Goodell, Margaret A %K Animals %K Cell Differentiation %K Cells, Cultured %K Cellular Senescence %K Chromatin Immunoprecipitation %K Epigenomics %K Hematopoietic Stem Cells %K Male %K Mice %K Transforming Growth Factor beta %X

To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-β signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging.

%B Cell Stem Cell %V 14 %P 673-88 %8 2014 May 01 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/24792119?dopt=Abstract %R 10.1016/j.stem.2014.03.002