Novel INHAT Repressor (NIR) is required for early lymphocyte development

Novel inhibitor of histone acetyltransferase repressor (NIR) is a transcriptional corepressor with inhibitor of histone acetyltransferase activity and is a potent suppressor of p53. Although NIR deficiency in mice leads to early embryonic lethality, lymphoid-restricted deletion resulted in the absence of double-positive CD4 ⁺CD8 ⁺ thymocytes, whereas bone-marrow-derived B cells were arrested at the B220 ⁺CD19 ⁻ pro–B-cell stage. V(D)J recombination was preserved in NIR-deficient DN3 double-negative thymocytes, suggesting that NIR does not affect p53 function in response to physiologic DNA breaks. Nevertheless, the combined deficiency of NIR and p53 provided rescue of DN3L double-negative thymocytes and their further differentiation to double- and single-positive thymocytes, whereas B cells in the marrow further developed to the B220 ⁺CD19 ⁺ pro–B-cell stage. Our results show that NIR cooperate with p53 to impose checkpoint for the generation of mature B and T lymphocytes. Significance Novel inhibitor of histone acetyltransferase repressor (NIR) is a transcriptional corepressor that can bind to p53 at promoters and suppress p53-transcriptional activity by inhibiting histone acetylation. We found that lymphoid-restricted deletion of NIR resulted in the absence of mature B and T lymphocytes, which is partially, but not completely, rescued by the combined deletion of p53 with NIR. Thus, NIR cooperates with p53 to impose a checkpoint for the generation of mature B and T lymphocytes in vivo. Further delineation of additional protein interactions with NIR may lead to the better understanding of the mechanisms that regulate cell-cycle regulation, apoptosis, and lymphocyte differentiation.