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Cell Res. 2018 Feb;28(2):204-220. doi: 10.1038/cr.2018.1. Epub 2018 Jan 9.

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

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Ludwig Institute for Cancer Research, 9500 Gilman Dr., La Jolla, CA 92093, USA.
Department of Medical Biochemistry and Biophysics, Division of Functional Genomics and Systems Biology, Karolinska Institutet, 171 65 Stockholm, Sweden.
Current address: Aptose Biosciences Inc., 3550 General Atomics Ct, San Diego, CA 92122, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, School of Medicine, Institute of Genomic Medicine, 9500 Gilman Dr., La Jolla, CA 92093, USA.


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.


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