KAP1 regulates gene networks controlling T-cell development and responsiveness

Francesca R Santoni De Sio, Isabelle Barde, Sandra Offner, Adamandia Kapopoulou, Andrea Corsinotti, Karolina Bojkowska, Raphaël Genolet, James H. Thomas, Immanuel F. Luescher, Daniel Pinschewer, Nicola Harris, Didier Trono

Research output: Contribution to journalArticle

Abstract

Chromatin remodeling at specific genomic loci controls lymphoid differentiation. Here, we investigated the role played in this process by Kruppelassociated 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 TGF 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.

Original languageEnglish
Pages (from-to)4561-4575
Number of pages15
JournalFASEB Journal
Volume26
Issue number11
DOIs
Publication statusPublished - Nov 2012

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Keywords

  • Adaptive immune cells
  • Epigenetics
  • KAP1
  • KRAB-ZFP
  • KRAB-ZFPassociated protein 1
  • Kruppelassociated box zinc finger proteins

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

De Sio, F. R. S., Barde, I., Offner, S., Kapopoulou, A., Corsinotti, A., Bojkowska, K., Genolet, R., Thomas, J. H., Luescher, I. F., Pinschewer, D., Harris, N., & Trono, D. (2012). KAP1 regulates gene networks controlling T-cell development and responsiveness. FASEB Journal, 26(11), 4561-4575. https://doi.org/10.1096/fj.12-206177