Chen Yongheng, Chen Chunxia, Zhang Zhe, Liu Chun-Chi, Johnson Matthew E, Espinoza Celso A, Edsall Lee E, Ren Bing, Zhou Xianghong Jasmine, Grant Struan F A, Wells Andrew D, Chen Lin
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital & State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410008, China Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania and The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
Nucleic Acids Res. 2015 Jan;43(2):1268-82. doi: 10.1093/nar/gku1373. Epub 2015 Jan 7.
FOXP3 is a lineage-specific transcription factor that is required for regulatory T cell development and function. In this study, we determined the crystal structure of the FOXP3 forkhead domain bound to DNA. The structure reveals that FOXP3 can form a stable domain-swapped dimer to bridge DNA in the absence of cofactors, suggesting that FOXP3 may play a role in long-range gene interactions. To test this hypothesis, we used circular chromosome conformation capture coupled with high throughput sequencing (4C-seq) to analyze FOXP3-dependent genomic contacts around a known FOXP3-bound locus, Ptpn22. Our studies reveal that FOXP3 induces significant changes in the chromatin contacts between the Ptpn22 locus and other Foxp3-regulated genes, reflecting a mechanism by which FOXP3 reorganizes the genome architecture to coordinate the expression of its target genes. Our results suggest that FOXP3 mediates long-range chromatin interactions as part of its mechanisms to regulate specific gene expression in regulatory T cells.
FOXP3是一种谱系特异性转录因子，是调节性T细胞发育和功能所必需的。在本研究中，我们确定了与DNA结合的FOXP3叉头结构域的晶体结构。该结构表明，在没有辅助因子的情况下，FOXP3可以形成稳定的结构域交换二聚体来桥接DNA，这表明FOXP3可能在长程基因相互作用中发挥作用。为了验证这一假设，我们使用环状染色体构象捕获结合高通量测序（4C-seq）来分析围绕已知的FOXP3结合位点Ptpn22的FOXP3依赖性基因组接触。我们的研究表明，FOXP3诱导Ptpn22位点与其他Foxp3调节基因之间的染色质接触发生显著变化，这反映了一种机制，即FOXP3通过该机制重组基因组结构以协调其靶基因的表达。我们的结果表明，FOXP3介导长程染色质相互作用，作为其在调节性T细胞中调节特定基因表达机制的一部分。
