H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

Stephen P. Methot; Jan Padeken; Giovanna Brancati; Peter Zeller; Colin E. Delaney; Dimos Gaidatzis; Hubertus Kohler; Alexander van Oudenaarden; Helge Großhans; Susan M. Gasser

doi:10.1038/s41556-021-00776-w

H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

Stephen P. Methot, Jan Padeken, Giovanna Brancati, Peter Zeller, Colin E. Delaney, Dimos Gaidatzis, Hubertus Kohler, Alexander van Oudenaarden, Helge Großhans, Susan M. Gasser^*

^*Corresponding author for this work

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Abstract

The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.

Original language	English
Pages (from-to)	1163-1175
Number of pages	13
Journal	Nature Cell Biology
Volume	23
Issue number	11
DOIs	https://doi.org/10.1038/s41556-021-00776-w
Publication status	Published - Nov 2021

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@article{e9ba2c1589d141f7b2652b4bbfb6763d,

title = "H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity",

abstract = "The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.",

author = "Methot, {Stephen P.} and Jan Padeken and Giovanna Brancati and Peter Zeller and Delaney, {Colin E.} and Dimos Gaidatzis and Hubertus Kohler and {van Oudenaarden}, Alexander and Helge Gro{\ss}hans and Gasser, {Susan M.}",

note = "Funding Information: We thank V. Kalck, A. Mattout, D. S. Cabianca and C. Schmid of the Gasser laboratory and L. Xu, I. Katic, S. Smallwood, S. Aluri, S. Thiry, L. Gelman and J. Eglinger from the FMI facilities for C. elegans, Genomics and Microscopy for discussion and support. Strains were provided by the Caenorhabditis Genetics Center (CGC), funded by NIH Office of Research Infrastructure Programs (grant no. P40 OD010440). We thank A. Brunet and R. Yeo for providing the enhancer strains. S.P.M. was supported by a long-term EMBO fellowship. G.B. was supported by a Boehringer Ingelheim Fonds PhD Fellowship. P.Z. was supported by a SNF Postdoc Mobility Fellowship and a HFSP postdoctoral fellowship. The Gasser laboratory is supported by the European Union{\textquoteright}s Horizon 2020 European Research Council Advanced grant (grant no. ERC-AdG 743312—Epiherigans) and thanks the Novartis Research Foundation for FMI core funding. A.v.O. also received funding from a European Research Council Advanced grant (grant no. ERC-AdG 742225-—IntScOmics) and Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) TOP award (grant no. NWO-CW 714.016.001). H.G. received funding from the SNSF National Center of Competence in Research RNA and Disease. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = nov,

doi = "10.1038/s41556-021-00776-w",

language = "English",

volume = "23",

pages = "1163--1175",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "11",

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T1 - H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

AU - Methot, Stephen P.

AU - Padeken, Jan

AU - Brancati, Giovanna

AU - Zeller, Peter

AU - Delaney, Colin E.

AU - Gaidatzis, Dimos

AU - Kohler, Hubertus

AU - van Oudenaarden, Alexander

AU - Großhans, Helge

AU - Gasser, Susan M.

N1 - Funding Information: We thank V. Kalck, A. Mattout, D. S. Cabianca and C. Schmid of the Gasser laboratory and L. Xu, I. Katic, S. Smallwood, S. Aluri, S. Thiry, L. Gelman and J. Eglinger from the FMI facilities for C. elegans, Genomics and Microscopy for discussion and support. Strains were provided by the Caenorhabditis Genetics Center (CGC), funded by NIH Office of Research Infrastructure Programs (grant no. P40 OD010440). We thank A. Brunet and R. Yeo for providing the enhancer strains. S.P.M. was supported by a long-term EMBO fellowship. G.B. was supported by a Boehringer Ingelheim Fonds PhD Fellowship. P.Z. was supported by a SNF Postdoc Mobility Fellowship and a HFSP postdoctoral fellowship. The Gasser laboratory is supported by the European Union’s Horizon 2020 European Research Council Advanced grant (grant no. ERC-AdG 743312—Epiherigans) and thanks the Novartis Research Foundation for FMI core funding. A.v.O. also received funding from a European Research Council Advanced grant (grant no. ERC-AdG 742225-—IntScOmics) and Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) TOP award (grant no. NWO-CW 714.016.001). H.G. received funding from the SNSF National Center of Competence in Research RNA and Disease. Publisher Copyright: © 2021, The Author(s).

PY - 2021/11

Y1 - 2021/11

N2 - The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.

AB - The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.

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DO - 10.1038/s41556-021-00776-w

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ER -

H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

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