Kwon Ho-Keun, Chen Hui-Min, Mathis Diane, Benoist Christophe
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Nat Immunol. 2017 Nov;18(11):1238-1248. doi: 10.1038/ni.3835. Epub 2017 Sep 11.
FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (T cells). Its mechanism of action, whether as an activator or a repressor, has remained unclear. Here, chromatin analysis showed that FoxP3 bound active enhancer elements, not repressed chromatin, around loci over- or under-expressed in T cells. We evaluated the impact of a panel of FoxP3 mutants on its transcriptional activity and interactions with DNA, transcriptional cofactors and chromatin. Computational integration, confirmed by biochemical interaction and size analyses, showed that FoxP3 existed in distinct multimolecular complexes. It was active and primarily an activator when complexed with the transcriptional factors RELA, IKZF2 and KAT5. In contrast, FoxP3 was inactive when complexed with the histone methyltransferase EZH2 and transcription factors YY1 and IKZF3. The latter complex partitioned to a peripheral region of the nucleus, as shown by super-resolution microscopy. Thus, FoxP3 acts in multimodal fashion to directly activate or repress transcription, in a context- and partner-dependent manner, to govern T cell phenotypes.
FoxP3决定调节性T细胞（T细胞）的转录特征和功能方面。其作用机制，无论是作为激活剂还是抑制剂，一直不清楚。在这里，染色质分析表明，FoxP3结合在T细胞中过表达或低表达基因座周围的活性增强子元件上，而不是结合在受抑制的染色质上。我们评估了一组FoxP3突变体对其转录活性以及与DNA、转录辅因子和染色质相互作用的影响。通过生化相互作用和大小分析证实的计算整合表明，FoxP3以不同的多分子复合物形式存在。当与转录因子RELA、IKZF2和KAT5复合时，它具有活性且主要是激活剂。相反，当与组蛋白甲基转移酶EZH2以及转录因子YY1和IKZF3复合时，FoxP3无活性。如超分辨率显微镜所示，后一种复合物定位于细胞核的外周区域。因此，FoxP3以多模式方式发挥作用，以依赖于环境和伙伴的方式直接激活或抑制转录，从而控制T细胞表型。
