Polycomb Group Protein YY1 Is an Essential Regulator of Hematopoietic Stem Cell Quiescence

Yin yang 1 (YY1) is a ubiquitous transcription factor and mammalian polycomb group protein (PcG) with important functions to regulate embryonic development, lineage differentiation, and cell proliferation. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that catalyze histone modifications. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Here, we demonstrate that a conditional knockout of Yy1 in hematopoietic stem cells (HSCs) decreases long-term repopulating activity and ectopic YY1 expression expands HSCs. Although the YY1 PcG domain is required for Igκ chain rearrangement in B cells, the YY1 mutant lacking the PcG domain retained the capacity to stimulate HSC self-renewal. YY1 deficiency deregulated the genetic network governing HSC cell proliferation and impaired stem cell factor/c-Kit signaling, disrupting mechanisms conferring HSC quiescence. These results reveal a mechanism for how a ubiquitously expressed transcriptional repressor mediates lineage-specific functions to control adult hematopoiesis. Lu et al. investigate the function of the polycomb group (PcG) protein YY1 in hematopoietic stem cells. Independent of its REPO domain/PcG function, YY1 promotes hematopoietic stem cell self-renewal and quiescence, suggesting that REPO domain/PcG function is not utilized in all contexts within the hematopoietic hierarchy.