MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (T_reg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements of the gene encoding the transcription factor Foxp3 that were looped to the MLL4-binding site and compromised both the thymic differentiation and the inducible differentiation of T_reg cells. We found that MLL4 catalyzed methylation of H3K4 at distant unbound enhancers via chromatin looping, which identifies a previously unknown mechanism for regulating the T cell enhancer landscape and affecting T_reg cell differentiation.

中文翻译：

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MLL4通过染色质循环为Foxp3诱导准备了增强子景观。

MLL4是组蛋白H3 Lys4（H3K4）-甲基化复合物的重要亚基。我们发现MLL4缺乏症损害了调节性T细胞（T _reg细胞）并导致推定的基因增强子的单甲基化H3K4（H3K4me1）和染色质相互作用大大降低，其中相当一部分不是MLL4的直接靶点，而是与MLL4结合位点相互作用的增强子。未与MLL4结合的增强子的H3K4me1和染色质相互作用的降低与远处相互作用区域的MLL4结合相关。上游MLL4结合位点的删除减少了H3K4me1在编码转录因子Foxp3的基因的调控元件上的丰度，该基因被环化到MLL4结合位点，并损害了胸腺分化和T _reg的诱导分化细胞。我们发现，MLL4通过染色质环催化在遥远的未结合增强子处催化H3K4的甲基化，这确定了调节T细胞增强子景观并影响T _reg细胞分化的未知机制。