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Integrated epigenomics reveal dysregulated chromatin landscapes in aged hematopoietic stem cells underlying aberrant transcription

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Age-associated hematopoietic stem cell (HSC) phenotypes contribute to myeloid lineage skewing, loss of reconstitution potential, and elevated risk of cancer transformation. To define specific epigenetic alterations associated with changed potential in old HSCs, we profiled transcriptomes, histone modifications, chromatin accessibility, and chromatin interactions of purified HSCs from young and aged mice. Uniquely, we have used a consistent immunophenotype to isolate stem cells and updated methodology to generate a compendium of epigenetic analyses to serve as a resource for studying the regulation of hematopoietic stem cells. Aged HSCs had globally decreased levels of active, permissive, and repressive histone modifications compared to young HSCs, though specific loci displayed age-associated increases. We classified HSC bivalent promoters with presence of both H3K27me3 and K3K4me3, and approximately twenty percent of domains had significant age-associated alterations with almost half of the modified bivalent promoters associated with HSC transcriptional alterations. The histone modification changes were accompanied by an overall more open chromatin landscape allowing for increased accessibility at functionally relevant transcription factor binding sites and aberrant expression of transposable elements in aged HSCs. The increased chromatin accessibility in aged HSCs was also accompanied by enrichment of H3K27ac levels at putative enhancer regions. Moreover, the loosened chromatin was associated with increased short-range and decreased long-range interactions in mostly heterochromatin regions, measured by Hi-C. These epigenomic data generated on a uniformly isolated population of HSCs provide a consensus library on changes associated with aging and define critical targets for restoration of youthful potential.

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