TY - JOUR
T1 - KAP1 regulates gene networks controlling T-cell development and responsiveness
AU - De Sio, Francesca R.Santoni
AU - Barde, Isabelle
AU - Offner, Sandra
AU - Kapopoulou, Adamandia
AU - Corsinotti, Andrea
AU - Bojkowska, Karolina
AU - Genolet, Raphaël
AU - Thomas, James H.
AU - Luescher, Immanuel F.
AU - Pinschewer, Daniel
AU - Harris, Nicola
AU - Trono, Didier
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
KW - Adaptive immune cells
KW - Epigenetics
KW - KAP1
KW - KRAB-ZFP
KW - KRAB-ZFPassociated protein 1
KW - Kruppelassociated box zinc finger proteins
UR - http://www.scopus.com/inward/record.url?scp=84868293703&partnerID=8YFLogxK
U2 - 10.1096/fj.12-206177
DO - 10.1096/fj.12-206177
M3 - Article
C2 - 22872677
AN - SCOPUS:84868293703
VL - 26
SP - 4561
EP - 4575
JO - The FASEB Journal
JF - The FASEB Journal
SN - 0892-6638
IS - 11
ER -