| First Author | Santoni de Sio FR | Year | 2012 |
| Journal | FASEB J | Volume | 26 |
| Issue | 11 | Pages | 4561-75 |
| PubMed ID | 22872677 | Mgi Jnum | J:193348 |
| Mgi Id | MGI:5468214 | Doi | 10.1096/fj.12-206177 |
| Citation | Santoni de Sio FR, et al. (2012) KAP1 regulates gene networks controlling T-cell development and responsiveness. FASEB J 26(11):4561-75 |
| abstractText | 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 TGFbeta 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. |
