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MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping.
Nature Immunology ( IF 27.7 ) Pub Date : 2017-Sep-01 , DOI: 10.1038/ni.3812
Katarzyna Placek , Gangqing Hu , Kairong Cui , Dunfang Zhang , Yi Ding , Ji-Eun Lee , Younghoon Jang , Chaochen Wang , Joanne Elizabeth Konkel , Jiuzhou Song , Chengyu Liu , Kai Ge , Wanjun Chen , Keji Zhao

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 (Treg 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 Treg 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 Treg cell differentiation.

中文翻译:

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。
更新日期:2017-09-06
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