Polycomb-Dependent H3K27me1 and H3K27me2 Regulate Active Transcription and Enhancer Fidelity

Karin J. Ferrari; Andrea Scelfo; Sri Ganesh Jammula; Alessandro Cuomo; Iros Barozzi; Alexandra Stützer; Wolfgang Fischle; Tiziana Bonaldi; Diego Pasini

doi:10.1016/j.molcel.2013.10.030

Polycomb-Dependent H3K27me1 and H3K27me2 Regulate Active Transcription and Enhancer Fidelity

Karin J. Ferrari, Andrea Scelfo, Sri Ganesh Jammula, Alessandro Cuomo, Iros Barozzi, Alexandra Stützer, Wolfgang Fischle, Tiziana Bonaldi, Diego Pasini^*

^*Corresponding author for this work

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

367 Scopus citations

Abstract

H3K27me3 is deposited at promoters by the preferential association of Polycomb repressive complex 2 (PRC2) with CpG-rich DNA elements regulating development by repressing gene transcription. H3K27 is also present in mono- and dimethylated states; however, the functional roles of H3K27me1 and H3K27me2 deposition remain poorly characterized. Here, we show that PRC2 activity is not only associated with H3K27me3 but also regulates all forms of H3K27 methylation in a spatially defined manner, contributing to different genomic functions in mouse embryonic stem cells. H3K27me1 accumulates within transcribed genes, promotes transcription, and is regulated by Setd2-dependent H3K36me3 deposition. Contrarily, H3K27me2 is present on approximately 70% of total histone H3 and is distributed in large chromatin domains, exerting protective functions by preventing firing of non-cell-type-specific enhancers. Considering that only 5%-10% of deregulated genes in PRC2-deficient cells are direct H3K27me3 targets, our data support an active role for all H3K27 methylated forms in regulating transcription and determining cell identity.

Original language	English (US)
Pages (from-to)	49-62
Number of pages	14
Journal	Molecular cell
Volume	53
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2013.10.030
State	Published - Jan 9 2014
Externally published	Yes

Bibliographical note

Funding Information:
We thank all members of the Pasini laboratory for helpful discussion; Hye Ryung Jung and Ole Nørregaard Jensen for MS data support; Gabriele Bucci, Davide Cittaro, Gioacchino Natoli, and Saverio Minucci for general support; Andrea Piunti for his comments; Anton Wutz for the mouse Eed KO ESCs; and Veronica Raker for help editing the manuscript. D.P. was supported by the Italian Association for Cancer Research and by the Italian Ministry of Health. T.B. was supported by grants from the Giovanni Armenise-Harvard Foundation Career Development Program, the Association of International Cancer Research, the Italian Association for Cancer Research, and the Cariplo Foundation. I.B. was supported by a fellowship of the Italian Cancer Research Foundation.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2013.10.030

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title = "Polycomb-Dependent H3K27me1 and H3K27me2 Regulate Active Transcription and Enhancer Fidelity",

abstract = "H3K27me3 is deposited at promoters by the preferential association of Polycomb repressive complex 2 (PRC2) with CpG-rich DNA elements regulating development by repressing gene transcription. H3K27 is also present in mono- and dimethylated states; however, the functional roles of H3K27me1 and H3K27me2 deposition remain poorly characterized. Here, we show that PRC2 activity is not only associated with H3K27me3 but also regulates all forms of H3K27 methylation in a spatially defined manner, contributing to different genomic functions in mouse embryonic stem cells. H3K27me1 accumulates within transcribed genes, promotes transcription, and is regulated by Setd2-dependent H3K36me3 deposition. Contrarily, H3K27me2 is present on approximately 70% of total histone H3 and is distributed in large chromatin domains, exerting protective functions by preventing firing of non-cell-type-specific enhancers. Considering that only 5%-10% of deregulated genes in PRC2-deficient cells are direct H3K27me3 targets, our data support an active role for all H3K27 methylated forms in regulating transcription and determining cell identity.",

author = "Ferrari, {Karin J.} and Andrea Scelfo and Jammula, {Sri Ganesh} and Alessandro Cuomo and Iros Barozzi and Alexandra St{\"u}tzer and Wolfgang Fischle and Tiziana Bonaldi and Diego Pasini",

note = "Funding Information: We thank all members of the Pasini laboratory for helpful discussion; Hye Ryung Jung and Ole N{\o}rregaard Jensen for MS data support; Gabriele Bucci, Davide Cittaro, Gioacchino Natoli, and Saverio Minucci for general support; Andrea Piunti for his comments; Anton Wutz for the mouse Eed KO ESCs; and Veronica Raker for help editing the manuscript. D.P. was supported by the Italian Association for Cancer Research and by the Italian Ministry of Health. T.B. was supported by grants from the Giovanni Armenise-Harvard Foundation Career Development Program, the Association of International Cancer Research, the Italian Association for Cancer Research, and the Cariplo Foundation. I.B. was supported by a fellowship of the Italian Cancer Research Foundation. ",

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AU - Ferrari, Karin J.

AU - Scelfo, Andrea

AU - Jammula, Sri Ganesh

AU - Cuomo, Alessandro

AU - Barozzi, Iros

AU - Stützer, Alexandra

AU - Fischle, Wolfgang

AU - Bonaldi, Tiziana

AU - Pasini, Diego

N1 - Funding Information: We thank all members of the Pasini laboratory for helpful discussion; Hye Ryung Jung and Ole Nørregaard Jensen for MS data support; Gabriele Bucci, Davide Cittaro, Gioacchino Natoli, and Saverio Minucci for general support; Andrea Piunti for his comments; Anton Wutz for the mouse Eed KO ESCs; and Veronica Raker for help editing the manuscript. D.P. was supported by the Italian Association for Cancer Research and by the Italian Ministry of Health. T.B. was supported by grants from the Giovanni Armenise-Harvard Foundation Career Development Program, the Association of International Cancer Research, the Italian Association for Cancer Research, and the Cariplo Foundation. I.B. was supported by a fellowship of the Italian Cancer Research Foundation.

PY - 2014/1/9

Y1 - 2014/1/9

N2 - H3K27me3 is deposited at promoters by the preferential association of Polycomb repressive complex 2 (PRC2) with CpG-rich DNA elements regulating development by repressing gene transcription. H3K27 is also present in mono- and dimethylated states; however, the functional roles of H3K27me1 and H3K27me2 deposition remain poorly characterized. Here, we show that PRC2 activity is not only associated with H3K27me3 but also regulates all forms of H3K27 methylation in a spatially defined manner, contributing to different genomic functions in mouse embryonic stem cells. H3K27me1 accumulates within transcribed genes, promotes transcription, and is regulated by Setd2-dependent H3K36me3 deposition. Contrarily, H3K27me2 is present on approximately 70% of total histone H3 and is distributed in large chromatin domains, exerting protective functions by preventing firing of non-cell-type-specific enhancers. Considering that only 5%-10% of deregulated genes in PRC2-deficient cells are direct H3K27me3 targets, our data support an active role for all H3K27 methylated forms in regulating transcription and determining cell identity.

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JF - Molecular cell

IS - 1

ER -

Polycomb-Dependent H3K27me1 and H3K27me2 Regulate Active Transcription and Enhancer Fidelity

Abstract

Bibliographical note

ASJC Scopus subject areas

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