Abstract
Senescence, a state of permanent cell cycle arrest, can be induced by DNA damage. This process, which was initially described in fibroblasts, is now recognized to occur in stem cells. It has been well characterized in cell lines, but there is currently very limited data available on human senescence in vivo. We recently reported that the expression of transposable elements (TE), including endogenous retroviruses, was up-regulated along with inflammatory genes in human senescent hematopoietic stem and progenitor cells (HSPCs) in vivo. The mechanism of regulation of TE expression is not completely understood, but changes in DNA methylation and chromatin modifications are known to alter their expression. In order to elucidate the molecular mechanisms for TE up-regulation after senescence of HSPCs, we employed whole-genome bisulfite sequencing in paired senescent and active human HSPCs in vivo from healthy subjects. We found that the senescent HSPCs exhibited hypomethylated regions in the genome, which were enriched for TEs. This is the first report characterizing the methylome of senescent human HSPCs.
Highlights
Aging is characterized by a progressive loss of organ function
Senescent human hematopoietic stem and progenitor cells (HSPCs) isolated from peripheral blood of healthy subjects In order to assess if epigenetic alterations such as changes in DNA methylation contributed to increased expression of transposable elements (TE) in senescent HSPCs, we subjected paired senescent and active HSPCs from 3 healthy humans to whole-genome bisulfite sequencing (WGBS)
Using the 2-dimensional Komogorov-Smirnov approach implemented in Metilene with cutoffs of 10% minimum difference, 10 CpGs and 10% FDR, we identified 61 differentially methylated regions (DMRs) in senescent vs. active HSPCs, of which 51 were hypo-methylated and 10 hyper-methylated (Additional file 1: Table S1)
Summary
The complex cellular process of stem cell aging likely contributes to the aging phenotype [1,2,3]. Cellular senescence, defined as a state of permanent cell cycle arrest, plays a distinct and important role in aging [4,5,6]. While the phenomenon of senescence was originally described in fibroblasts, it has been shown to occur in stem and progenitor cells, with senescent hematopoietic, hepatic, endothelial, and skeletal muscle progenitor populations identified [8,9,10,11,12,13,14,15]. Comprehensive molecular features of human senescent cells in vivo have not been well investigated. We recently identified and isolated circulating senescent HSPCs from healthy human subjects and showed that their transcriptome had elevated expression of transposable elements (TEs) [16]
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