| First Author | Wagatsuma K | Year | 2015 |
| Journal | J Immunol | Volume | 195 |
| Issue | 4 | Pages | 1804-14 |
| PubMed ID | 26195811 | Mgi Jnum | J:279650 |
| Mgi Id | MGI:6363884 | Doi | 10.4049/jimmunol.1302456 |
| Citation | Wagatsuma K, et al. (2015) STAT5 Orchestrates Local Epigenetic Changes for Chromatin Accessibility and Rearrangements by Direct Binding to the TCRgamma Locus. J Immunol 195(4):1804-14 |
| abstractText | The transcription factor STAT5, which is activated by IL-7R, controls chromatin accessibility and rearrangements of the TCRgamma locus. Although STAT-binding motifs are conserved in Jgamma promoters and Egamma enhancers, little is known about their precise roles in rearrangements of the TCRgamma locus in vivo. To address this question, we established two lines of Jgamma1 promoter mutant mice: one harboring a deletion in the Jgamma1 promoter, including three STAT motifs (Jgamma1P(Delta/Delta)), and the other carrying point mutations in the three STAT motifs in that promoter (Jgamma1P(mS/mS)). Both Jgamma1P(Delta/Delta) and Jgamma1P(mS/mS) mice showed impaired recruitment of STAT5 and chromatin remodeling factor BRG1 at the Jgamma1 gene segment. This resulted in severe and specific reduction in germline transcription, histone H3 acetylation, and histone H4 lysine 4 methylation of the Jgamma1 gene segment in adult thymus. Rearrangement and DNA cleavage of the segment were severely diminished, and Jgamma1 promoter mutant mice showed profoundly decreased numbers of gammadelta T cells of gamma1 cluster origin. Finally, compared with controls, both mutant mice showed a severe reduction in rearrangements of the Jgamma1 gene segment, perturbed development of gammadelta T cells of gamma1 cluster origin in fetal thymus, and fewer Vgamma3(+) dendritic epidermal T cells. Furthermore, interaction with the Jgamma1 promoter and Egamma1, a TCRgamma enhancer, was dependent on STAT motifs in the Jgamma1 promoter. Overall, this study strongly suggests that direct binding of STAT5 to STAT motifs in the Jgamma promoter is essential for local chromatin accessibility and Jgamma/Egamma chromatin interaction, triggering rearrangements of the TCRgamma locus. |
