Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation

Delphine Douillet; Christie C. Sze; Caila Ryan; Andrea Piunti; Avani P. Shah; Michal Ugarenko; Stacy A. Marshall; Emily J. Rendleman; Didi Zha; Kathryn A. Helmin; Zibo Zhao; Kaixiang Cao; Marc A. Morgan; Benjamin D. Singer; Elizabeth T. Bartom; Edwin R. Smith; Ali Shilatifard

doi:10.1038/s41588-020-0618-1

Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation

Delphine Douillet, Christie C. Sze, Caila Ryan, Andrea Piunti, Avani P. Shah, Michal Ugarenko, Stacy A. Marshall, Emily J. Rendleman, Didi Zha, Kathryn A. Helmin, Zibo Zhao, Kaixiang Cao, Marc A. Morgan, Benjamin D. Singer, Elizabeth T. Bartom, Edwin R. Smith, Ali Shilatifard^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

Abstract

The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4 trimethylation underlies transcriptional regulation on MLL2/COMPASS targets.

Original language	English (US)
Pages (from-to)	615-625
Number of pages	11
Journal	Nature Genetics
Volume	52
Issue number	6
DOIs	https://doi.org/10.1038/s41588-020-0618-1
State	Published - Jun 1 2020

Funding

We thank the Shilatifard laboratory members for helpful suggestions and discussions. K.A.H. and B.D.S. are supported by NIH K08HL128867. C.C.S. is supported, in part, by the NIH Predoctoral to Postdoctoral Transition Award F99CA234945. K.C. is supported, in part, by the NIH Pathway to Independence Award K99HD094906. A.P. is supported by the NIH Pathway to Independence Award K99CA234434. E.R.S. is supported by NIH R50CA211428. We thank N. J. Ethen for the graphical representation of the model (Fig. 8). Studies in the Shilatifard laboratory related to COMPASS are supported by the NCI Outstanding Investigator Award R35CA197569.

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Genetics

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41588-020-0618-1

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Douillet, D., Sze, C. C., Ryan, C., Piunti, A., Shah, A. P., Ugarenko, M., Marshall, S. A., Rendleman, E. J., Zha, D., Helmin, K. A., Zhao, Z., Cao, K., Morgan, M. A., Singer, B. D., Bartom, E. T., Smith, E. R., & Shilatifard, A. (2020). Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation. Nature Genetics, 52(6), 615-625. https://doi.org/10.1038/s41588-020-0618-1

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abstract = "The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4 trimethylation underlies transcriptional regulation on MLL2/COMPASS targets.",

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Douillet, D, Sze, CC, Ryan, C, Piunti, A, Shah, AP, Ugarenko, M, Marshall, SA, Rendleman, EJ, Zha, D, Helmin, KA, Zhao, Z, Cao, K, Morgan, MA, Singer, BD , Bartom, ET, Smith, ER & Shilatifard, A 2020, 'Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation', Nature Genetics, vol. 52, no. 6, pp. 615-625. https://doi.org/10.1038/s41588-020-0618-1

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AU - Douillet, Delphine

AU - Sze, Christie C.

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AU - Piunti, Andrea

AU - Shah, Avani P.

AU - Ugarenko, Michal

AU - Marshall, Stacy A.

AU - Rendleman, Emily J.

AU - Zha, Didi

AU - Helmin, Kathryn A.

AU - Zhao, Zibo

AU - Cao, Kaixiang

AU - Morgan, Marc A.

AU - Singer, Benjamin D.

AU - Bartom, Elizabeth T.

AU - Smith, Edwin R.

AU - Shilatifard, Ali

PY - 2020/6/1

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N2 - The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4 trimethylation underlies transcriptional regulation on MLL2/COMPASS targets.

AB - The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4 trimethylation underlies transcriptional regulation on MLL2/COMPASS targets.

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Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation

Abstract

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UN SDGs

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