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MLL3/MLL4 Histone Methyltranferase Activity Dependent Chromatin Organization at Enhancers during Embryonic Stem Cell Differentiation

Naoki Kubo, Rong Hu, Zhen Ye, Bing Ren
doi: https://doi.org/10.1101/2021.03.17.435905
Naoki Kubo
1Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
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Rong Hu
1Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
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Zhen Ye
1Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
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Bing Ren
1Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
2Center for Epigenomics, Department of Cellular and Molecular Medicine, Moores Cancer Center and Institute of Genome Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
3Ludwig Institute for Cancer Research, La Jolla, CA, USA
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  • For correspondence: biren@health.ucsd.edu
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SUMMARY

MLL3 (KMT2C) and MLL4 (KMT2D), the major mono-methyltransferases of histone H3 lysine 4 (H3K4), are required for cellular differentiation and embryonic development in mammals. We previously observed that MLL3/4 promote long-range chromatin interactions at enhancers, however, it is still unclear how their catalytic activities contribute to enhancer-dependent gene activation in mammalian cell differentiation. To address this question, we mapped histone modifications, long-range chromatin contacts as well as gene expression in MLL3/4 catalytically deficient mouse embryonic stem (ES) cells undergoing differentiation toward neural precursor cells. We showed that MLL3/4 activities are responsible for deposition of H3K4me1 modification and formation of long-range enhancer-promoter contacts at a majority of putative enhancers gained during cell differentiation, but are dispensable for most candidate enhancers found in undifferentiated ES cells that persist through differentiation. While transcriptional induction at most genes is unaltered in the MLL3/4 catalytically deficient cells, genes making more contacts with MLL3/4-dependent putative enhancers are disproportionately affected. These results support that MLL3/4 contributes to cellular differentiation through histone-methyltransferase-activity dependent induction of enhancer-promoter contacts and transcriptional activation at a subset of lineage-specific genes.

Competing Interest Statement

B.R. is a co-founder of Arima Genomics, Inc. and Epigenome Technologies, Inc..

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 18, 2021.
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MLL3/MLL4 Histone Methyltranferase Activity Dependent Chromatin Organization at Enhancers during Embryonic Stem Cell Differentiation
Naoki Kubo, Rong Hu, Zhen Ye, Bing Ren
bioRxiv 2021.03.17.435905; doi: https://doi.org/10.1101/2021.03.17.435905
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MLL3/MLL4 Histone Methyltranferase Activity Dependent Chromatin Organization at Enhancers during Embryonic Stem Cell Differentiation
Naoki Kubo, Rong Hu, Zhen Ye, Bing Ren
bioRxiv 2021.03.17.435905; doi: https://doi.org/10.1101/2021.03.17.435905

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