title: KAP1 regulates gene networks controlling T-cell development and responsiveness.
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.
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Santoni de Sio
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barde
authors.forename: Sandra
authors.initials: S
authors.lastname: Offner
authors.forename: Adamandia
authors.initials: A
authors.lastname: Kapopoulou
authors.forename: Andrea
authors.initials: A
authors.lastname: Corsinotti
authors.forename: Karolina
authors.initials: K
authors.lastname: Bojkowska
authors.forename: Raphaël
authors.initials: R
authors.lastname: Genolet
authors.forename: James H
authors.initials: JH
authors.lastname: Thomas
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinschewer
authors.forename: Nicola
authors.initials: N
authors.lastname: Harris
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010802:Phylogeny; D011485:Protein Binding; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D059467:Transcriptome; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D009687:Nuclear Proteins; D012097:Repressor Proteins; D012313:RNA; D004247:DNA; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28