YY1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells from Premature Aging

Hematopoietic stem cells (HSCs) undergo functional decline with age, characterized by myeloid-biased differentiation, loss of quiescence, and altered metabolic homeostasis. The molecular mechanisms driving these changes remain incompletely understood. Yin Yang 1 (YY1) is a multifunctional transcription factor and mammalian Polycomb group (PcG) protein that recruits PcG complexes to specific genomic loci via its 26–amino acid REPO (Recruitment of Polycomb) domain. To define the role of YY1 PcG function in adult HSCs, we generated a conditional YY1 REPO domain knockout mouse model ( Yy1 −/ΔREPO ). Deletion of the REPO domain led to premature HSC aging, with expansion of immunophenotypic HSCs but loss of long-term self-renewal capacity. Yy1 −/ΔREPO HSCs exhibited myeloid-biased output, expansion of myeloid-primed multipotent progenitors, increased myeloid colony formation, and an elevated myeloid-to-lymphoid ratio in peripheral blood. These cells displayed reduced quiescence, elevated reactive oxygen species, increased mitochondrial oxidative capacity, and enhanced β-galactosidase activity—hallmarks of cellular aging. RNA-seq demonstrated dysregulation of gene networks governing HSC metabolism. Together, these findings establish YY1 PcG activity as a key epigenetic mechanism that preserves metabolic quiescence, sustains long-term self-renewal, and delays HSC aging. Our studies reveal a fundamental PcG-dependent epigenetic mechanism that dictate cell fate decisions and function decline during HSC aging.