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 ( <i>Yy1 ^-/ΔREPO</i> ) by CRISPR/Cas9 to further dissect the underlying mechanisms. <i>Yy1 ^-/ΔREPO</i> 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. <i>Yy1 ^-/ΔREPO</i> 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 <i>Yy1 ^-/ΔREPO</i> DN3 T cells. The YY1 REPO deletion leads to downregulation of DNA demethylase enzyme <i>Tet1</i> and <i>Tet2</i> expressions in DN3 cells with no change of <i>Tet3</i> . Pharmacologic inhibition of TET catalytic activity blocked DN-to-DP progression at the DN3 stage, whereas re-expression of TET2 catalytic domain in <i>Yy1 ^-/ΔREPO</i> 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.