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bioRxiv · 10.64898/2026.01.28.702390

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

Saka, S.·Lee, J. P.·Wang, Y.·Liu, P.·Liu, Y.·Hong, C.·Kuehnl, A.·Rui, L.·Atchison, M. L.·Pan, X.
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Abstract

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-/{Delta}REPO). Deletion of the REPO domain led to premature HSC aging, with expansion of immunophenotypic HSCs but loss of long-term self-renewal capacity. Yy1-/{Delta}REPO 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 {beta}-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.

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Saka, S., Lee, J. P., Wang, Y., Liu, P., Liu, Y., Hong, C., Kuehnl, A., Rui, L., Atchison, M. L., Pan, X.. 2026-01-29. YY1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells from Premature Aging. https://doi.org/10.64898/2026.01.28.702390

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