Yin Yang 1-Dependent PcG Function is Essential for TET2 Expression and Early T cell Development

Yin Yang 1 (YY1) is a multifunctional transcription factor and mammalian Polycomb Group (PcG) protein critical for lymphocyte development. While YY1 is essential for early T-cell development and survival, the underlying epigenetic mechanisms by which YY1 regulates early T-cell development are not fully understood. Herein, we utilized the YY1 PcG function conditional knockout mouse model ( Yy1 ^-/ΔREPO ) by CRISPR/Cas9 to further dissect the underlying mechanisms. Yy1 ^-/ΔREPO mice show early T cell development blockage at the double-negative (DN) 3 to single positive T cell transition with expansion of the DN3 population. Yy1 ^-/ΔREPO DN3 cells are highly proliferative, but more prone to apoptosis, leading to reduced single positive T cells output. The genetic network governing T cell differentiation is deregulated in Yy1 ^-/ΔREPO DN3 T cells. The YY1 REPO deletion leads to downregulation of DNA demethylase enzyme Tet1 and Tet2 expressions in DN3 cells with no change of Tet3 . Pharmacologic inhibition of TET catalytic activity blocked DN-to-DP progression at the DN3 stage, whereas re-expression of TET2 catalytic domain in Yy1 ^-/ΔREPO DN thymocytes partially rescued T cell differentiation. Together, our study demonstrates that YY1-mediated PcG function is essential for the DN3 to SP T cell transition and YY1-TET2 axis promotes proper DN3 differentiation.