KAP1 regulates gene networks controlling T-cell development and responsiveness

Santoni de Sio, Francesca R. and Barde, Isabelle and Offner, Sandra and Kapopoulou, Adamandia and Corsinotti, Andrea and Bojkowska, Karolina and Genolet, Raphaël and Thomas, James H. and Luescher, Immanuel F. and Pinschewer, Daniel and Harris, Nicola and Trono, Didier. (2012) KAP1 regulates gene networks controlling T-cell development and responsiveness. FASEB Journal, 26 (11). pp. 4561-4575.

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Medical Microbiology > Experimental Virology (Pinschewer)
UniBasel Contributors:Pinschewer, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Federation of American Society of Experimental Biology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:15 Dec 2020 12:08
Deposited On:15 Dec 2020 12:08

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