Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers

• DOI: 10.1038/cr.2018.1
• Publication Date: 2018-01-09T06:41:58Z
• Authors: Jian Yan; Shi-An A Chen; Andrea Local; Tristin Liu; Yunjiang Qiu; Kristel M Dorighi; Sebastian Preissl; Chloe M Rivera; Chaochen Wang; Zhen Ye; Kai Ge; Ming Hu; Joanna Wysocka; Bing Ren
• Keywords: 0301 basic medicine; Chromosomal Proteins, Non-Histone; Sequence Analysis, RNA; SOXB1 Transcription Factors; Gene Expression; Cell Cycle Proteins; Cell Differentiation; Histone-Lysine N-Methyltransferase; Methylation; Chromatin; DNA-Binding Proteins; Histones; Mice; 03 medical and health sciences; Enhancer Elements, Genetic; Animals; Promoter Regions, Genetic; Cohesins; Embryonic Stem Cells; In Situ Hybridization, Fluorescence

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.