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Differential DNA methylation encodes proliferation and senescence programs in human adipose-derived mesenchymal stem cells

ABSTRACT: Adipose tissue-derived mesenchymal stem cells (ASC’s) constitute a vital population of multipotent cells capable of differentiating into end-organ tissues. However, scientific endeavors to harness the regenerative potential of ASC’s for regenerative medicine are currently limited by an incomplete understanding of the mechanisms that determine cell-lineage commitment and stemness. In the current study, we used reduced representation bisulfite sequencing (RRBS) analysis to identify epigenetic gene targets and cellular processes that are responsive to 5-azathioprine, a potent inducer of DNA methylation. In this manner, we describe specific changes to DNA methylation of ASCs to identify the critical pathways associated with ASC differentiation . We identified 4,797 differentially-methylated regions (FDR < 0.05) associated with 3,625 genes. Gene set enrichment analysis of the differentially-methylated target promoters identified phagocytosis, type 2 diabetes mellitus, and metabolic pathways as disproportionately hypomethylated, whereas adipocyte differentiation was the top most-enriched pathway to represent genes with hyper-methylated promoters. Interestingly, ZNF11 and ELK4 gene response elements were identified as genomic features most affected by DNA hypo- and hyper-methylation, respectively. Although further validation is needed, the implications of this pilot analysis provide the basis for understanding how epigenetic mechanisms influence the metabolic phenotype, and ultimately regenerative capacity, of ASC’s.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139157 | GEO | 2020/03/19

REPOSITORIES: GEO

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Project description:<p>Aberrant DNA methylation changes are known to occur during prostate cancer progression beginning with precursor lesions. Utilizing fifty nanograms of genomic DNA in Methylplex-Next Generation Sequencing (M-NGS) we mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2). Peaks were located from mapped reads obtained in each sequencing run using a Hidden Markov Model (HMM)-based algorithm previously used for Chip-Seq data analysis(<a href="http://www.sph.umich.edu/csg/qin/HPeak">http://www.sph.umich.edu/csg/qin/HPeak</a>). The total methylation events in intergenic/intronic regions between benign adjacent and cancer tissues were comparable. Promoter CGI methylation gradually increased from -12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues and approximately 20% of all CpG islands (CGIs) (68,508) were methylated in tissues. We observed distinct patterns in promoter methylation around transcription start sites, where methylation occurred directly on the CGIs, flanking regions and on CGI sparse promoters. Among the 6,691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer specific and several previously studied targets were among them. A novel cancer specific DMR in WFDC2 promoter showed 77% methylation in cancer (17/22), 100% methylation in transformed prostate cell lines (6/6), none in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested a role for DNA methylation in alternate transcription start site utilization. While methylated promoters containing CGIs had mutually exclusive H3K4me3 modification, the histone mark was absent in CGI sparse promoters. Finally, we observed difference in methylation of LINE-1 elements between transcription factor ERG positive and negative cancers. The comprehensive methylome map presented here will further our understanding of epigenetic regulation of the prostate cancer genome. Overall Design: We mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2) from fifty nanograms of genomic DNA using Methylplex-Next Generation Sequencing (M-NGS). For replicate analysis in cell lines, a total of 4 runs were completed for PrEC prostate normal cell line, and 5 runs were completed for LNCaP prostate cancer cell line. For tissue samples, 2 benign prostate samples were sequenced twice on Illumina next generation sequencing platform to access overall repeatability of M-NGS.</p>

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Differential DNA methylation encodes proliferation and senescence programs in human adipose-derived mesenchymal stem cells

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