Transient reprogramming limits AP-1-associated chromatin opening and transposable element activation to preserve hematopoietic stem cell function during aging and stress
Hematopoietic stem cell (HSC) aging is associated with epigenetic remodeling, yet the molecular mechanisms driving these changes, their overlap with stress-induced alterations, and whether this course can be durably reset remain incompletely understood. Here, we show that transient induction of the Yamanaka factors OCT4, SOX2, KLF4, and MYC in young mice durably delays and partially reverses…
Hematopoietic stem cell aging linked to epigenetic changes, but the mechanisms behind these alterations and their reversibility remain unclear. Researchers demonstrated that briefly activating Yamanaka factors OCT4, SOX2, KLF4, and MYC in young mice delays and partially reverses HSC aging. This intervention improved hematopoietic reconstitution, reduced myeloid bias, and limited DNA damage.
Multi-omic studies showed reduced chromatin accessibility at AP-1-rich regulatory areas, less AP-1-driven transcription, and decreased transposable element (TE) activity. Blocking AP-1 with drugs halted TE activation and HSC clonogenicity loss induced by LPS stress. In aged mice, inhibiting reverse transcriptase reduced DNA damage and enhanced HSC function, indicating TE activity's role in HSC decline.
These results suggest AP-1-associated chromatin remodeling as a potential mechanism connecting inflammatory stress, TE activation, and HSC aging.
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