Yin Yang 1 Promotes Thymocyte Survival by Downregulating p53

Abstract

Yin Yang 1 (YY1) is a zinc finger protein that functions as a transcriptional activator or repressor and participates in multiple biological processes, including development and tumorigenesis. To investigate the role of YY1 in developing T cells, we used mouse models that depleted YY1 at two distinct stages of thymocyte development. When YY1 was depleted in CD4−CD8− double negative (DN) thymocytes, development to the CD4+CD8+ double positive (DP) stage was impaired, due to increased apoptosis that prevented expansion of post–β-selection thymocytes. When YY1 was depleted in DP thymocytes, they underwent increased cell-autonomous apoptosis in vitro and displayed a shorter lifespan in vivo, as judged by their ability to undergo secondary Vα-to-Jα recombination. Mechanistically, we found that the increased apoptosis in YY1-deficient thymocytes was attributed to overexpression of p53, because concurrent loss of p53 completely rescued the developmental defects of YY1-deficient thymocytes. These results indicated that YY1 functions as a critical regulator of thymocyte survival and that it does so by suppressing the expression of p53.

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

“…Consistent with the Ki-67/DAPI results, Yy1 −/− LT-HSC and ST-HSC failed to establish normal quiescence with an increased proportion of BrdU + cells ( Figure 6B ). As YY1 can regulate apoptosis ( Affar et al, 2006 ; Chen et al, 2016 ; Sui et al, 2004 ), we tested whether YY1 deficiency impacted HSC apoptosis. Early and late apoptotic cells were stained with AnnexinV/DAPI.…”

“…Multiple transcription factors and epigenetic regulators function as intrinsic regulators of HSC quiescence. YY1, a multifunctional transcription factor and a PcG protein, plays critical roles in B and T lymphocyte development ( Chen et al, 2016 ; Kleiman et al, 2016 ; Liu et al, 2007 ; Zaprazna and Atchison, 2012 ). While many PcG proteins have important roles in HSC self-renewal and lineage differentiation, YY1 is one of a few mammalian PcG proteins with intrinsic sequence-specific DNA binding activity ( Atchison et al, 2003 ; Srinivasan and Atchison, 2004 ).…”

Coexpression of YY1 Is Required to Elaborate the Effector Functions Controlled by PLZF in NKT Cells

“…YY1 modulates chromatin structure and thus gene expression by mediating the formation of enhancer-promoter loops and by recruiting HAT and HDAC proteins to specific loci (18). Conditional deletion of YY1 at the double-negative stage results in a major block in thymocyte development (19). Interestingly, however, the loss of YY1 in thymocytes is compensated for by simultaneous deletion of p53 (19).…”

EZH2 Regulates the Developmental Timing of Effectors of the Pre–Antigen Receptor Checkpoints

“…Rag1 −/− or Cd3 γ −/− mice), which fail β-selection but can by-pass this checkpoint when Trp53 (p53) is deleted or mutated(6, 7). Stabilization of p53 prevents B and T cell development beyond the pre-antigen receptor checkpoints, as evidenced in mice lacking genes that directly regulate p53 at the transcriptional (WIP1(8, 9), MYSM1(10)), post-transcriptional (CNOT(11)), translational (RPL22(12, 13), MIZ1(14, 15)), or post-translational (YY1(16–18), BCL11A(19), NIR(20)) levels. Remarkably, B and T cell maturation are substantially restored in these mice upon deletion of p53.…”