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KAP1 regulates gene networks controlling T-cell development and responsiveness.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2012
Author Santoni de Sio Francesca R, Barde Isabelle, Offner Sandra, Kapopoulou Adamandia, Corsinotti Andrea, Bojkowska Karolina, Genolet Raphaël, Thomas James H, Luescher Immanuel F, Pinschewer Daniel, Harris Nicola, Trono Didier,
Project Innate defenses against retroelements
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Original article (peer-reviewed)

Journal FASEB journal : official publication of the Federation of American Societies for Experimental Biolog
Volume (Issue) 26(11)
Page(s) 4561 - 75
Title of proceedings FASEB journal : official publication of the Federation of American Societies for Experimental Biolog
DOI 10.1096/fj.12-206177

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.
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