Yin Yang 1-dependent TET2 regulation is essential for early T cell development

Abstract Yin Yang 1 (YY1) is a multifunctional transcription factor and mammalian Polycomb Group (PcG) protein critical for lymphocyte development. While YY1 is required for early T-cell development and survival, the underlying mechanisms remain incompletely defined. Herein, we utilize the YY1 REPO domain conditional knockout mouse model ( Yy1 -/ΔREPO ) to further dissect the YY1-PcG domain dependent epigenetic regulation in early T cell development. Yy1 -/ΔREPO mice show a developmental block at the double-negative (DN) 3 to DN4 T cell transition, with expansion of the DN3 population and reduced TCRβ + DN4 T cells. The genetic network governing T cell differentiation is dysregulated in Yy1 -/ΔREPO DN3 T cells. YY1 binds directly to the Tet2 promoter, and deletion of the YY1 REPO domain leads to downregulation of the DNA demethylase TET2 in DN3 T cells. Although deletion of the YY1 REPO domain does not impair YY1 binding at the Tet2 promoter, H3K4me3 enrichment at the promoter is reduced. Pharmacologic inhibition of TET catalytic activity in wild-type DN thymocytes partially recapitulates the developmental defects in Yy1 -/ΔREPO DN thymocytes, whereas re-expression of TET2 catalytic domain in Yy1 -/ΔREPO DN thymocytes partially rescues T cell development. Collectively, these findings reveal a previously unappreciated link between YY1 REPO domain-dependent regulation and TET2-mediated epigenetic control during early T-cell development.