Epigenomic Landscape of Aging in Human Hematopoietic Stem Cells
DOI:
https://doi.org/10.5281/zenodo.22687903Keywords:
hematopoietic stem cells, aging, DNA methylation, chromatin accessibility, clonal hematopoiesis, DNMT3A, myeloid bias, ATAC-seqAbstract
Human hematopoietic stem cells (HSCs) accumulate a well-documented functional bias toward myeloid output
and a reduced capacity for balanced, multilineage reconstitution as they age, changes that underlie the rising
incidence of myeloid malignancy and clonal haematopoiesis in older adults, yet the epigenomic reorganisation
accompanying this functional drift has not been comprehensively resolved in purified human HSCs at single-base
and single-locus resolution across a broad adult age range. We profiled DNA methylation (whole-genome bisulfite
sequencing) and chromatin accessibility (ATAC-seq) in immunophenotypically purified HSCs
(Lin-CD34+CD38-CD90+CD45RA-) from 42 healthy human bone marrow donors spanning 21 to 78 years of age,
paired with RNA sequencing from the same cells to link epigenomic and transcriptional change. Genome-wide
methylation showed a bidirectional age-associated pattern, with 8,412 differentially methylated regions (DMRs)
gaining methylation and 5,076 losing methylation across the age range (FDR<0.05); hypermethylated DMRs were
strongly enriched at polycomb-marked developmental transcription factor loci, including multiple lymphoid-lineage
regulators, while hypomethylated DMRs were enriched at myeloid-lineage enhancers. ATAC-seq identified a
concordant, though only partially overlapping, shift in chromatin accessibility, with 6,124 regions gaining and 3,847
losing accessibility with age, and joint analysis showed that accessibility gain was significantly more common than
expected by chance at myeloid enhancers that also lost DNA methylation with age (odds ratio 3.4, P<0.001).
DNMT3A and TET2, the two genes most frequently mutated in age-related clonal haematopoiesis, showed
progressive age-associated transcriptional decline in aged HSCs even in donors without detectable clonal
haematopoiesis-associated mutations, and their target loci were disproportionately represented among
age-hypermethylated DMRs, linking normal age-related epigenetic drift mechanistically to the loci most commonly
disrupted by acquired clonal haematopoiesis mutations. These data provide a comprehensive, multi-omic
epigenomic atlas of human HSC aging and nominate a compact panel of age-discriminating methylation loci with
potential utility as a cell-intrinsic haematopoietic aging biomarker.
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