Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks

Frank W. Schmitges; Archana B. Prusty; Mahamadou Faty; Alexandra Stützer; Gondichatnahalli M. Lingaraju; Jonathan Aiwazian; Ragna Sack; Daniel Hess; Ling Li; Shaolian Zhou; Richard D. Bunker; Urs Wirth; Tewis Bouwmeester; Andreas Bauer; Nga Ly-Hartig; Kehao Zhao; Homan Chan; Justin Gu; Heinz Gut; Wolfgang Fischle; Jürg Müller; Nicolas H. Thomä

doi:10.1016/j.molcel.2011.03.025

Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks

Frank W. Schmitges, Archana B. Prusty, Mahamadou Faty, Alexandra Stützer, Gondichatnahalli M. Lingaraju, Jonathan Aiwazian, Ragna Sack, Daniel Hess, Ling Li, Shaolian Zhou, Richard D. Bunker, Urs Wirth, Tewis Bouwmeester, Andreas Bauer, Nga Ly-Hartig, Kehao Zhao, Homan Chan, Justin Gu, Heinz Gut, Wolfgang FischleJürg Müller^*, Nicolas H. Thomä

^*Corresponding author for this work

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

557 Scopus citations

Abstract

The Polycomb repressive complex 2 (PRC2) confers transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3). Here, we examined how PRC2 is modulated by histone modifications associated with transcriptionally active chromatin. We provide the molecular basis of histone H3 N terminus recognition by the PRC2 Nurf55-Su(z)12 submodule. Binding of H3 is lost if lysine 4 in H3 is trimethylated. We find that H3K4me3 inhibits PRC2 activity in an allosteric fashion assisted by the Su(z)12 C terminus. In addition to H3K4me3, PRC2 is inhibited by H3K36me2/3 (i.e., both H3K36me2 and H3K36me3). Direct PRC2 inhibition by H3K4me3 and H3K36me2/3 active marks is conserved in humans, mouse, and fly, rendering transcriptionally active chromatin refractory to PRC2 H3K27 trimethylation. While inhibition is present in plant PRC2, it can be modulated through exchange of the Su(z)12 subunit. Inhibition by active chromatin marks, coupled to stimulation by transcriptionally repressive H3K27me3, enables PRC2 to autonomously template repressive H3K27me3 without overwriting active chromatin domains.

Original language	English (US)
Pages (from-to)	330-341
Number of pages	12
Journal	Molecular cell
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2011.03.025
State	Published - May 6 2011
Externally published	Yes

Bibliographical note

Funding Information:
We thank Dirk Schübeler, Antoine Peters, and Susan Gasser for helpful discussions. We thank Norman Kairies and Andrea Scrima for crystallographic support, Maja Koehn and Victoria McParland for advice on peptide synthesis and purification, and Vladimir Rybin for help with ITC measurements. We are also grateful to Ernest Laue for providing us with the plasmid for the GST-H4 construct. Funding in the laboratory of N.H.T. is provided by Association for International Cancer Research grant 10-0292 and the Novartis Research Foundation. F.W.S. gratefully acknowledges funding from the Schering Foundation and the Studienstiftung des deutschen Volkes. A.B.P., N.L.-H., and J.M. were supported by European Molecular Biology Laboratory.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2011.03.025

Cite this

Schmitges, F. W., Prusty, A. B., Faty, M., Stützer, A., Lingaraju, G. M., Aiwazian, J., Sack, R., Hess, D., Li, L., Zhou, S., Bunker, R. D., Wirth, U., Bouwmeester, T., Bauer, A., Ly-Hartig, N., Zhao, K., Chan, H., Gu, J., Gut, H., ... Thomä, N. H. (2011). Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks. Molecular cell, 42(3), 330-341. https://doi.org/10.1016/j.molcel.2011.03.025

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title = "Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks",

abstract = "The Polycomb repressive complex 2 (PRC2) confers transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3). Here, we examined how PRC2 is modulated by histone modifications associated with transcriptionally active chromatin. We provide the molecular basis of histone H3 N terminus recognition by the PRC2 Nurf55-Su(z)12 submodule. Binding of H3 is lost if lysine 4 in H3 is trimethylated. We find that H3K4me3 inhibits PRC2 activity in an allosteric fashion assisted by the Su(z)12 C terminus. In addition to H3K4me3, PRC2 is inhibited by H3K36me2/3 (i.e., both H3K36me2 and H3K36me3). Direct PRC2 inhibition by H3K4me3 and H3K36me2/3 active marks is conserved in humans, mouse, and fly, rendering transcriptionally active chromatin refractory to PRC2 H3K27 trimethylation. While inhibition is present in plant PRC2, it can be modulated through exchange of the Su(z)12 subunit. Inhibition by active chromatin marks, coupled to stimulation by transcriptionally repressive H3K27me3, enables PRC2 to autonomously template repressive H3K27me3 without overwriting active chromatin domains.",

author = "Schmitges, {Frank W.} and Prusty, {Archana B.} and Mahamadou Faty and Alexandra St{\"u}tzer and Lingaraju, {Gondichatnahalli M.} and Jonathan Aiwazian and Ragna Sack and Daniel Hess and Ling Li and Shaolian Zhou and Bunker, {Richard D.} and Urs Wirth and Tewis Bouwmeester and Andreas Bauer and Nga Ly-Hartig and Kehao Zhao and Homan Chan and Justin Gu and Heinz Gut and Wolfgang Fischle and J{\"u}rg M{\"u}ller and Thom{\"a}, {Nicolas H.}",

note = "Funding Information: We thank Dirk Sch{\"u}beler, Antoine Peters, and Susan Gasser for helpful discussions. We thank Norman Kairies and Andrea Scrima for crystallographic support, Maja Koehn and Victoria McParland for advice on peptide synthesis and purification, and Vladimir Rybin for help with ITC measurements. We are also grateful to Ernest Laue for providing us with the plasmid for the GST-H4 construct. Funding in the laboratory of N.H.T. is provided by Association for International Cancer Research grant 10-0292 and the Novartis Research Foundation. F.W.S. gratefully acknowledges funding from the Schering Foundation and the Studienstiftung des deutschen Volkes. A.B.P., N.L.-H., and J.M. were supported by European Molecular Biology Laboratory. ",

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month = may,

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doi = "10.1016/j.molcel.2011.03.025",

language = "English (US)",

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Schmitges, FW, Prusty, AB, Faty, M, Stützer, A, Lingaraju, GM, Aiwazian, J, Sack, R, Hess, D, Li, L, Zhou, S, Bunker, RD, Wirth, U, Bouwmeester, T, Bauer, A, Ly-Hartig, N, Zhao, K, Chan, H, Gu, J, Gut, H, Fischle, W, Müller, J & Thomä, NH 2011, 'Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks', Molecular cell, vol. 42, no. 3, pp. 330-341. https://doi.org/10.1016/j.molcel.2011.03.025

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T1 - Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks

AU - Schmitges, Frank W.

AU - Prusty, Archana B.

AU - Faty, Mahamadou

AU - Stützer, Alexandra

AU - Lingaraju, Gondichatnahalli M.

AU - Aiwazian, Jonathan

AU - Sack, Ragna

AU - Hess, Daniel

AU - Li, Ling

AU - Zhou, Shaolian

AU - Bunker, Richard D.

AU - Wirth, Urs

AU - Bouwmeester, Tewis

AU - Bauer, Andreas

AU - Ly-Hartig, Nga

AU - Zhao, Kehao

AU - Chan, Homan

AU - Gu, Justin

AU - Gut, Heinz

AU - Fischle, Wolfgang

AU - Müller, Jürg

AU - Thomä, Nicolas H.

N1 - Funding Information: We thank Dirk Schübeler, Antoine Peters, and Susan Gasser for helpful discussions. We thank Norman Kairies and Andrea Scrima for crystallographic support, Maja Koehn and Victoria McParland for advice on peptide synthesis and purification, and Vladimir Rybin for help with ITC measurements. We are also grateful to Ernest Laue for providing us with the plasmid for the GST-H4 construct. Funding in the laboratory of N.H.T. is provided by Association for International Cancer Research grant 10-0292 and the Novartis Research Foundation. F.W.S. gratefully acknowledges funding from the Schering Foundation and the Studienstiftung des deutschen Volkes. A.B.P., N.L.-H., and J.M. were supported by European Molecular Biology Laboratory.

PY - 2011/5/6

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N2 - The Polycomb repressive complex 2 (PRC2) confers transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3). Here, we examined how PRC2 is modulated by histone modifications associated with transcriptionally active chromatin. We provide the molecular basis of histone H3 N terminus recognition by the PRC2 Nurf55-Su(z)12 submodule. Binding of H3 is lost if lysine 4 in H3 is trimethylated. We find that H3K4me3 inhibits PRC2 activity in an allosteric fashion assisted by the Su(z)12 C terminus. In addition to H3K4me3, PRC2 is inhibited by H3K36me2/3 (i.e., both H3K36me2 and H3K36me3). Direct PRC2 inhibition by H3K4me3 and H3K36me2/3 active marks is conserved in humans, mouse, and fly, rendering transcriptionally active chromatin refractory to PRC2 H3K27 trimethylation. While inhibition is present in plant PRC2, it can be modulated through exchange of the Su(z)12 subunit. Inhibition by active chromatin marks, coupled to stimulation by transcriptionally repressive H3K27me3, enables PRC2 to autonomously template repressive H3K27me3 without overwriting active chromatin domains.

AB - The Polycomb repressive complex 2 (PRC2) confers transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3). Here, we examined how PRC2 is modulated by histone modifications associated with transcriptionally active chromatin. We provide the molecular basis of histone H3 N terminus recognition by the PRC2 Nurf55-Su(z)12 submodule. Binding of H3 is lost if lysine 4 in H3 is trimethylated. We find that H3K4me3 inhibits PRC2 activity in an allosteric fashion assisted by the Su(z)12 C terminus. In addition to H3K4me3, PRC2 is inhibited by H3K36me2/3 (i.e., both H3K36me2 and H3K36me3). Direct PRC2 inhibition by H3K4me3 and H3K36me2/3 active marks is conserved in humans, mouse, and fly, rendering transcriptionally active chromatin refractory to PRC2 H3K27 trimethylation. While inhibition is present in plant PRC2, it can be modulated through exchange of the Su(z)12 subunit. Inhibition by active chromatin marks, coupled to stimulation by transcriptionally repressive H3K27me3, enables PRC2 to autonomously template repressive H3K27me3 without overwriting active chromatin domains.

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DO - 10.1016/j.molcel.2011.03.025

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AN - SCOPUS:79955494277

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EP - 341

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JF - Molecular cell

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Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks

Abstract

Bibliographical note

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