KAP1 regulates gene networks controlling T-cell development and responsiveness.
FASEB J, 2012/11;26(11):4561-75.
Santoni de Sio FR[1], Barde I, Offner S, Kapopoulou A, Corsinotti A, Bojkowska K, Genolet R, Thomas JH, Luescher IF, Pinschewer D, Harris N, Trono D
Affiliations
PMID: 22872677DOI: 10.1096/fj.12-206177
Impact factor: 5.834
Abstract
Chromatin remodeling at specific genomic loci controls lymphoid differentiation. Here, we investigated the role played in this process by Kruppel-associated box (KRAB)-associated protein 1 (KAP1), the universal cofactor of KRAB-zinc finger proteins (ZFPs), a tetrapod-restricted family of transcriptional repressors. T-cell-specific Kap1-deleted mice displayed a significant expansion of immature thymocytes, imbalances in CD4(+)/CD8(+) cell ratios, and altered responses to TCR and TGFβ stimulation when compared to littermate KAP1 control mice. Transcriptome and chromatin studies revealed that KAP1 binds T-cell-specific cis-acting regulatory elements marked by the H3K9me3 repressive mark and enriched in Ikaros/NuRD complexes. Also, KAP1 directly controls the expression of several genes involved in TCR and cytokine signaling. Among these, regulation of FoxO1 seems to play a major role in this system. Likely responsible for tethering KAP1 to at least part of its genomic targets, a small number of KRAB-ZFPs are selectively expressed in T-lymphoid cells. These results reveal the so far unsuspected yet important role of KAP1-mediated epigenetic regulation in T-lymphocyte differentiation and activation.
MeSH terms
Animals; Binding Sites; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; DNA; Epigenesis, Genetic; Gene Expression Regulation; Mice; Mice, Knockout; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Phenotype; Phylogeny; Protein Binding; RNA; Repressor Proteins; T-Lymphocytes; Transcriptome; Tripartite Motif-Containing Protein 28
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