A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element

Veronika A. Herzog; Adelheid Lempradl; Johanna Trupke; Helena Okulski; Christina Altmutter; Frank Ruge; Bernd Boidol; Stefan Kubicek; Gerald Schmauss; Karin Aumayr; Marius Ruf; Andrew Pospisilik; Andrew Dimond; Hasene Basak Senergin; Marcus L. Vargas; Jeffrey A. Simon; Leonie Ringrose

doi:10.1038/ng.3058

A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element

Veronika A. Herzog, Adelheid Lempradl, Johanna Trupke, Helena Okulski, Christina Altmutter, Frank Ruge, Bernd Boidol, Stefan Kubicek, Gerald Schmauss, Karin Aumayr, Marius Ruf, Andrew Pospisilik, Andrew Dimond, Hasene Basak Senergin, Marcus L. Vargas, Jeffrey A. Simon, Leonie Ringrose

Genetics, Cell Biology and Development (CBS)

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

87 Scopus citations

Abstract

Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. Here we show that a switch in forward and reverse noncoding transcription from the Drosophila melanogaster vestigial (vg) PRE/TRE switches the status of the element between silencing (induced by the forward strand) and activation (induced by the reverse strand). In vitro, both noncoding RNAs inhibit PRC2 histone methyltransferase activity, but, in vivo, only the reverse strand binds PRC2. Overexpression of the reverse strand evicts PRC2 from chromatin and inhibits its enzymatic activity. We propose that the interaction of RNAs with PRC2 is differentially regulated in vivo, allowing regulated inhibition of local PRC2 activity. Genome-wide analysis shows that strand switching of noncoding RNAs occurs at several hundred Polycomb-binding sites in fly and vertebrate genomes. This work identifies a previously unreported and potentially widespread class of PRE/TREs that switch function by switching the direction of noncoding RNA transcription.

Original language	English (US)
Pages (from-to)	973-981
Number of pages	9
Journal	Nature Genetics
Volume	46
Issue number	9
DOIs	https://doi.org/10.1038/ng.3058
State	Published - 2014

Bibliographical note

Funding Information:
We thank S. Gasser for discussions and for critical reading of the manuscript. We thank M. Rehmsmeier and members of our laboratories for discussions, P. Pasierbek for advice and training on imaging, P.A. Steffen (IMBA) for the GFP and E(z)øGFP constructs, C. Ehrhardt and E. Dworschak for technical assistance, B. Dickson (Janelia Farm) for the enGAL4 driver line, J.M. Dura (Institute of Human Genetics, Montpelier, France) for the daGAL4 driver line, I. Tamir (CSF Vienna) for the bioinformatics analysis of ChIP-seq data and sharing the ‘Fuge’ algorithm, F. Bantignies (Institute of Human Genetics, Montpelier, France) for advice on three-dimensional DNA FISH, R. Jones (Dedman College, Southern Methodist University) for providing antibody to E(Z) and the Vienna Campus Support Facility (CSF) for library preparation, deep sequencing and the purification of Drosophila PRC2. This work was funded by the Austrian Academy of Sciences, by European Community grants European Union Framework Programme 6 Network of Excellence ‘The Epigenome’ (to L.R.) and the European Union Framework Programme 7 Network of Excellence ‘Epigenesys’ (to L.R.), and by an FWF Austrian Science Fund grant (P21525-B20 to L.R.).

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© 2014 Nature America, Inc. All rights reserved.

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Herzog, V. A., Lempradl, A., Trupke, J., Okulski, H., Altmutter, C., Ruge, F., Boidol, B., Kubicek, S., Schmauss, G., Aumayr, K., Ruf, M., Pospisilik, A., Dimond, A., Senergin, H. B., Vargas, M. L., Simon, J. A., & Ringrose, L. (2014). A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element. Nature Genetics, 46(9), 973-981. https://doi.org/10.1038/ng.3058

Herzog, VA, Lempradl, A, Trupke, J, Okulski, H, Altmutter, C, Ruge, F, Boidol, B, Kubicek, S, Schmauss, G, Aumayr, K, Ruf, M, Pospisilik, A, Dimond, A, Senergin, HB, Vargas, ML, Simon, JA & Ringrose, L 2014, 'A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element', Nature Genetics, vol. 46, no. 9, pp. 973-981. https://doi.org/10.1038/ng.3058

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title = "A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element",

abstract = "Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. Here we show that a switch in forward and reverse noncoding transcription from the Drosophila melanogaster vestigial (vg) PRE/TRE switches the status of the element between silencing (induced by the forward strand) and activation (induced by the reverse strand). In vitro, both noncoding RNAs inhibit PRC2 histone methyltransferase activity, but, in vivo, only the reverse strand binds PRC2. Overexpression of the reverse strand evicts PRC2 from chromatin and inhibits its enzymatic activity. We propose that the interaction of RNAs with PRC2 is differentially regulated in vivo, allowing regulated inhibition of local PRC2 activity. Genome-wide analysis shows that strand switching of noncoding RNAs occurs at several hundred Polycomb-binding sites in fly and vertebrate genomes. This work identifies a previously unreported and potentially widespread class of PRE/TREs that switch function by switching the direction of noncoding RNA transcription.",

author = "Herzog, {Veronika A.} and Adelheid Lempradl and Johanna Trupke and Helena Okulski and Christina Altmutter and Frank Ruge and Bernd Boidol and Stefan Kubicek and Gerald Schmauss and Karin Aumayr and Marius Ruf and Andrew Pospisilik and Andrew Dimond and Senergin, {Hasene Basak} and Vargas, {Marcus L.} and Simon, {Jeffrey A.} and Leonie Ringrose",

note = "Funding Information: We thank S. Gasser for discussions and for critical reading of the manuscript. We thank M. Rehmsmeier and members of our laboratories for discussions, P. Pasierbek for advice and training on imaging, P.A. Steffen (IMBA) for the GFP and E(z){\o}GFP constructs, C. Ehrhardt and E. Dworschak for technical assistance, B. Dickson (Janelia Farm) for the enGAL4 driver line, J.M. Dura (Institute of Human Genetics, Montpelier, France) for the daGAL4 driver line, I. Tamir (CSF Vienna) for the bioinformatics analysis of ChIP-seq data and sharing the {\textquoteleft}Fuge{\textquoteright} algorithm, F. Bantignies (Institute of Human Genetics, Montpelier, France) for advice on three-dimensional DNA FISH, R. Jones (Dedman College, Southern Methodist University) for providing antibody to E(Z) and the Vienna Campus Support Facility (CSF) for library preparation, deep sequencing and the purification of Drosophila PRC2. This work was funded by the Austrian Academy of Sciences, by European Community grants European Union Framework Programme 6 Network of Excellence {\textquoteleft}The Epigenome{\textquoteright} (to L.R.) and the European Union Framework Programme 7 Network of Excellence {\textquoteleft}Epigenesys{\textquoteright} (to L.R.), and by an FWF Austrian Science Fund grant (P21525-B20 to L.R.). Publisher Copyright: {\textcopyright} 2014 Nature America, Inc. All rights reserved.",

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AU - Herzog, Veronika A.

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AU - Trupke, Johanna

AU - Okulski, Helena

AU - Altmutter, Christina

AU - Ruge, Frank

AU - Boidol, Bernd

AU - Kubicek, Stefan

AU - Schmauss, Gerald

AU - Aumayr, Karin

AU - Ruf, Marius

AU - Pospisilik, Andrew

AU - Dimond, Andrew

AU - Senergin, Hasene Basak

AU - Vargas, Marcus L.

AU - Simon, Jeffrey A.

AU - Ringrose, Leonie

N1 - Funding Information: We thank S. Gasser for discussions and for critical reading of the manuscript. We thank M. Rehmsmeier and members of our laboratories for discussions, P. Pasierbek for advice and training on imaging, P.A. Steffen (IMBA) for the GFP and E(z)øGFP constructs, C. Ehrhardt and E. Dworschak for technical assistance, B. Dickson (Janelia Farm) for the enGAL4 driver line, J.M. Dura (Institute of Human Genetics, Montpelier, France) for the daGAL4 driver line, I. Tamir (CSF Vienna) for the bioinformatics analysis of ChIP-seq data and sharing the ‘Fuge’ algorithm, F. Bantignies (Institute of Human Genetics, Montpelier, France) for advice on three-dimensional DNA FISH, R. Jones (Dedman College, Southern Methodist University) for providing antibody to E(Z) and the Vienna Campus Support Facility (CSF) for library preparation, deep sequencing and the purification of Drosophila PRC2. This work was funded by the Austrian Academy of Sciences, by European Community grants European Union Framework Programme 6 Network of Excellence ‘The Epigenome’ (to L.R.) and the European Union Framework Programme 7 Network of Excellence ‘Epigenesys’ (to L.R.), and by an FWF Austrian Science Fund grant (P21525-B20 to L.R.). Publisher Copyright: © 2014 Nature America, Inc. All rights reserved.

PY - 2014

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N2 - Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. Here we show that a switch in forward and reverse noncoding transcription from the Drosophila melanogaster vestigial (vg) PRE/TRE switches the status of the element between silencing (induced by the forward strand) and activation (induced by the reverse strand). In vitro, both noncoding RNAs inhibit PRC2 histone methyltransferase activity, but, in vivo, only the reverse strand binds PRC2. Overexpression of the reverse strand evicts PRC2 from chromatin and inhibits its enzymatic activity. We propose that the interaction of RNAs with PRC2 is differentially regulated in vivo, allowing regulated inhibition of local PRC2 activity. Genome-wide analysis shows that strand switching of noncoding RNAs occurs at several hundred Polycomb-binding sites in fly and vertebrate genomes. This work identifies a previously unreported and potentially widespread class of PRE/TREs that switch function by switching the direction of noncoding RNA transcription.

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A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element

Abstract

Bibliographical note

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