Abstract
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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Acknowledgements
We would like to thank the Ren Lab members Drs David Gorkin, Tingting Du, Miao Yu, Jason Guoqiang Li, as well as Drs Shicai Fan (UCSD) and Xi Wang (DKFZ, Germany) for comments during manuscript preparation. We are also very grateful to Samantha Kuan and Dr Bin Li for technical assistance. We thank UCSD Neuroscience Microscopy Shared Facility (NS047101) for FISH imaging and the Murre Lab (UCSD) for sharing protocols and discussions for FISH assay. This work was supported by the Ludwig Institute for Cancer Research (BR), NIH (P50 GM085764-04 to BR, U54DK107977 to BR and MH, and R01 GM112720 to JW), an International Postdoc fellowship from the Swedish Vetenskapsrådet (537-2014-6796 to JY) and HHMI (JW).
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Supplementary information
Supplementary information, Figure S1
Mll3/4 Deficient mESCs Reveal Lost Interaction between Sox2 Gene Body and SE, Related to Figure 1 (PDF 248 kb)
Supplementary information, Figure S2
Mll3/4 Are Required for Genome-wide Deposition of H3K4me1 at promoter-distal Enhancers, Related to Figure 1 (PDF 403 kb)
Supplementary information, Figure S3
H3K4me1 does not Affect Global Contact Frequency but is Required for FIREs, Related to Figure 2 (PDF 381 kb)
Supplementary information, Figure S4
H3K4me1 is Required for FIREs, Related to Figure 2 (PDF 1868 kb)
Supplementary information, Figure S6
Change of H3K4me1 is Associated with Change of Cohesin Binding, Related to Figure 5 (PDF 458 kb)
Supplementary information, Figure S7
Super-enhancer Call Using H3K27ac ChIP-seq Data, Related to Figure 6 (PDF 329 kb)
Supplementary information, Table S1
H3K4me1 peaks (XLSX 4492 kb)
Supplementary information, Table S2
FIRE score (XLSX 894 kb)
Supplementary information, Table S3
H3K27ac peaks in different group I-IV (XLSX 379 kb)
Supplementary information, Table S4
Super-enhancer (XLSX 157 kb)
Supplementary information, Table S5
Primers used in 4C-seq and shRNA knockdown and qPCR (XLSX 13 kb)
Supplementary information, Table S6
Antibodies (XLSX 11 kb)
Supplementary information, Table S7
Overview statictics of single cell RNA-seq (XLSX 13 kb)
Supplementary information, Table S8
Gene expression values (log2 transformed RPKM) in Wild type and DKO mESC during NPC differentiation, as shown in Figure 5C. (XLSX 3049 kb)
Supplementary information, Data S1
EXTENDED EXPERIMENTAL PROCEDURE (PDF 352 kb)
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Yan, J., Chen, SA., Local, A. et al. Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. Cell Res 28, 204–220 (2018). https://doi.org/10.1038/cr.2018.1
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DOI: https://doi.org/10.1038/cr.2018.1
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