FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (T_reg 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_reg 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_reg cell phenotypes.

中文翻译：

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不同的分子复合物介导FoxP3的转录诱导和抑制。

FoxP3调节调节性T细胞（T _reg细胞）的转录特征和功能方面。它的作用机制，无论是作为激活物还是抑制物，都还不清楚。在这里，染色质分析表明，FoxP3在T _reg中过表达或过表达的基因座周围结合了活性增强子元件，而不是抑制的染色质细胞。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的相互作用的影响。通过生化相互作用和大小分析证实的计算整合表明，FoxP3存在于不同的多分子复合物中。与转录因子RELA，IKZF2和KAT5复合时，它是有活性的，并且主要是激活剂。相反，当与组蛋白甲基转移酶EZH2和转录因子YY1和IKZF3复合时，FoxP3没有活性。后者的复合物分配到细胞核的外围区域，如超分辨率显微镜所示。因此，FoxP3以多峰形式起作用，以上下文和伴侣依赖性方式直接激活或抑制转录，从而控制T _reg细胞表型。