Molecular Determinants for Polycomb Group Protein YY1 Control of Hematopoietic Stem Cell Quiescence

Hematopoietic stem cells (HSCs) are undifferentiated, long-lived cells that give rise to lineage-specific progenitors and retain their stem cell identity by undergoing self-renewal. Adult HSCs can remain in a quiescent state for a prolonged time, and quiescence is a fundamental characteristic of adult bone marrow-resident HSCs. A precisely regulated cell cycle is required for HSC-mediated generation of mature hematopoietic cells, while preventing stem cell exhaustion. 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-specific regulation is achieved by PcG proteins. Herein, we conditionally deleted Yy1 in mouse hematopoietic cells (Yy1^f/f Mx1-Cre) and demonstrated that Yy1 deficiency decreases hematopoietic stem cells (HSCs) long-term repopulating activity. Moreever, ectopic YY1 expression expands HSCs. Yy1^-/- mice were pancytopenic with a significantly shorter median survival time compared with wild type mice. YY1 deficiency deregulated the genetic network governing HSC proliferation and impaired Stem Cell Factor (SCF) /c-Kit signaling, thus disrupting mechanisms conferring HSC quiescence. As our prior study demonstrated that YY1 PcG function is required for Igκ chain rearrangement in early B cell development, we evaluated the role of YY1 PcG function in HSC self-renewal and addressed whether the requirement for YY1 PcG function is context-dependent in adult hematopoiesis. Ectopic expression of a YY1 mutant lacking the PcG function (YY1ΔREPO) in Yy1^-/- mice rescued SCF/c-Kit signaling, HSC quiescence and maintained the capacity to stimulate HSC self-renewal. Thus, YY1 regulates adult hematopoiesis in both PcG-dependent and independent manners. These results reveal a unique mechanism for how a ubiquitously expressed transcriptional repressor mediates lineage-specific functions to control adult hematopoiesis. Currently, we are testing how YY1 differentially controls HSCs and B cells via PcG-independent and -dependent mechanisms respectively.