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Novel INHAT repressor (NIR) is required for early lymphocyte development.

ABSTRACT: 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.

SUBMITTER: Ma CA

PROVIDER: S-EPMC4183277 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Novel INHAT repressor (NIR) is required for early lymphocyte development.

Ma Chi A CA Pusso Antonia A Wu Liming L Zhao Yongge Y Hoffmann Victoria V Notarangelo Luigi D LD Fowlkes B J BJ Jain Ashish A

Proceedings of the National Academy of Sciences of the United States of America 20140908 38

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-n ...[more]

PMID: 25201955

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Project description:Cortical development is a tightly spatiotemporally regulated process in which cell-fate specification is accompanied by stable resetting of transcriptional programs. However, the full repertoire of transcriptional regulators orchestrating such transcriptome changes remains largely incomprehensive. Applying a bioinformatics predictive approach we aimed to identify novel transcription factors contriuting to transcriptional reprogramming during embryonic neurogenesis and identified the neuronal tissue specific transcription factor St18 to be essential for neurogenesis in vitro and in vivo. We find that embryonic stem cells deficient for St18 are not able to efficiently differentiate along neuronal lineage and St18 depleted cells in the developing cortex do not elongate in shape and reside in the VZ/SVZ region but display premature expression of the upper layer neuronal marker Satb2. Relation of St18 binding to genes deregulated upon St18 depletion in vivo revealed St18 to function as transcriptional repressor at the time when neurogenesis is initiated. St18 ensures efficient onset of cortical neurogenesis by inhibiting expression of the self-renewal maintaining factor Hes1 that represses differentiation genes in neuronal progenitors as well as downregulation of genes that are essential for differentiation into mesodermal and endodermal lineage such as Lama5, Traf4 and Tab1. Furthermore we find this transcriptional repressor to be bound to genes that are important for later stages of neurogenesis when the neuronal circuitry is established likely to keep them in repressed state in the time window of neurogenesis when they are not yet required. These genes important for axon guidance and neurite outgrowth are subsequently prematurely upregulated in St18 depleted cortical cells. We further observe St18 to be bound to a significant fraction of intergenic enhancers where it regulates expression of nearest genes that Our data establish St18 as a novel transcriptional regulator during early onset of cortical neurogenesis that is essential to ensure timely expression kinetics of phase and lineage specific genes.

Dataset Information

Novel INHAT repressor (NIR) is required for early lymphocyte development.

Publications

Novel INHAT repressor (NIR) is required for early lymphocyte development.

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