Histone H3 lysine 4 monomethylation modulates longrange chromatin interactions at enhancers

Long-range chromatin interactions between enhancers and promoters are essential for transcription of many developmentally controlled genes in mammals and other metazoans. Currently, the exact mechanisms that connect distal enhancers to their specific target promoters remain to be fully elucidated. Here, we show that the enhancer-specific histone H3 lysine 4 monomethylation (H3K4me1) and the histone methyltransferases MLL3 and MLL4 (MLL3/4) play an active role in this process. We demonstrate that in differentiating mouse embryonic stem cells, MLL3/4-dependent deposition of H3K4me1 at enhancers correlates with increased levels of chromatin interactions, whereas loss of this histone modification leads to reduced levels of chromatin interactions and defects in gene activation during differentiation. H3K4me1 facilitates recruitment of the Cohesin complex, a known regulator of chromatin organization, to chromatin in vitro and in vivo, providing a potential mechanism for MLL3/4 to promote chromatin interactions between enhancers and promoters. Taken together, our results support a role for MLL3/4-dependent H3K4me1 in orchestrating long-range chromatin interactions at enhancers in mammalian cells. Examination of chromatin loop interactions in 3 cell types.

增强子与启动子之间的远程染色质相互作用，对于哺乳动物及其他后生动物中众多发育调控基因的转录过程至关重要。目前，将远端增强子与其特异性靶启动子关联起来的确切机制仍有待完全阐明。本研究表明，增强子特异性组蛋白H3赖氨酸4单甲基化（H3K4me1）以及组蛋白甲基转移酶MLL3与MLL4（MLL3/4）在该过程中发挥积极作用。我们证实，在分化中的小鼠胚胎干细胞中，MLL3/4依赖的增强子区域H3K4me1沉积与染色质相互作用水平升高呈正相关；而该组蛋白修饰的缺失则会导致染色质相互作用水平降低，并引发分化过程中基因激活的缺陷。H3K4me1可促进黏连蛋白复合体（Cohesin complex，一种已知的染色质组织调控因子）在体外及体内与染色质的结合，这为MLL3/4介导增强子与启动子之间的染色质相互作用提供了潜在机制。综上，本研究结果证实，依赖MLL3/4的H3K4me1在哺乳动物细胞中参与调控增强子区域的远程染色质相互作用。本研究对3种细胞类型中的染色质环相互作用进行了检测分析。