title: Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging.
abstract: The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging.
authors: Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02116, USA.
authors: Isabel
authors: I
authors: Beerman
authors: Christoph
authors: C
authors: Bock
authors: Brian S
authors: BS
authors: Garrison
authors: Zachary D
authors: ZD
authors: Smith
authors: Hongcang
authors: H
authors: Gu
authors: Alexander
authors: A
authors: Meissner
authors: Derrick J
authors: DJ
authors: Rossi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D016615:Telomere / Q000378:metabolism
chemical_list: D063151:Polycomb Repressive Complex 2