A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities

Eric Conway; Emilia Jerman; Evan Healy; Shinsuke Ito; Daniel Holoch; Giorgio Oliviero; Orla Deevy; Eleanor Glancy; Darren J. Fitzpatrick; Marlena Mucha; Ariane Watson; Alan M. Rice; Paul Chammas; Christine Huang; Indigo Pratt-Kelly; Yoko Koseki; Manabu Nakayama; Tomoyuki Ishikura; Gundula Streubel; Kieran Wynne; Karsten Hokamp; Aoife McLysaght; Claudio Ciferri; Luciano Di Croce; Gerard Cagney; Raphaël Margueron; Haruhiko Koseki; Adrian P. Bracken

doi:10.1016/j.molcel.2018.03.005

A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities

Eric Conway, Emilia Jerman, Evan Healy, Shinsuke Ito, Daniel Holoch, Giorgio Oliviero, Orla Deevy, Eleanor Glancy, Darren J. Fitzpatrick, Marlena Mucha, Ariane Watson, Alan M. Rice, Paul Chammas, Christine Huang, Indigo Pratt-Kelly, Yoko Koseki, Manabu Nakayama, Tomoyuki Ishikura, Gundula Streubel, Kieran WynneKarsten Hokamp, Aoife McLysaght, Claudio Ciferri, Luciano Di Croce, Gerard Cagney, Raphaël Margueron, Haruhiko Koseki, Adrian P. Bracken

Department of Life Sciences

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

108 Citations (SciVal)

Abstract

The polycomb repressive complex 2 (PRC2) consists of core subunits SUZ12, EED, RBBP4/7, and EZH1/2 and is responsible for mono-, di-, and tri-methylation of lysine 27 on histone H3. Whereas two distinct forms exist, PRC2.1 (containing one polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2), little is known about their differential functions. Here, we report the discovery of a family of vertebrate-specific PRC2.1 proteins, “PRC2 associated LCOR isoform 1” (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and in vivo and is essential for mouse development. Pali1 and Aebp2 define mutually exclusive, antagonistic PRC2 subtypes that exhibit divergent H3K27-tri-methylation activities. The balance of these PRC2.1/PRC2.2 activities is required for the appropriate regulation of polycomb target genes during differentiation. PALI1/2 potentially link polycombs with transcriptional co-repressors in the regulation of cellular identity during development and in cancer. Pali1 and Pali2 form a new family of vertebrate-specific proteins that bind PRC2. Conway et al. show that Pali1 promotes PRC2 methyltransferase activity and defines a distinct PRC2.1 subtype essential for mouse development. They also establish that the balance of PRC2.1 and PRC2.2 activities is essential for proper regulation of polycomb target genes.

Original language	English
Pages (from-to)	408-421.e8
Number of pages	14
Journal	Molecular Cell
Volume	70
Issue number	3
Early online date	5 Apr 2018
DOIs	https://doi.org/10.1016/j.molcel.2018.03.005
Publication status	Published - 3 May 2018

Funding

We thank members of the Bracken lab for helpful discussions and critical reading of the manuscript. We also thank A. Fisher, A. Wutz, and N. Brockdorff for Jarid2 , Eed , and Aebp2 knockout ESCs, respectively. We thank R. Liefke, Y. Shi, and A. Leitner for sharing data and A. Flaus for advice on the characterization of the PIP domain. We also acknowledge support of the Spanish Ministry of Economy and Competitiveness ( BFU2016-75008-P ) to LDC. Work in the Bracken Lab is supported by Science Foundation Ireland under the SFI Investigators Programme ( SFI/16/IA/4562 ) and the BBSRC-SFI ( SFI/17/BBSRC/3415 ), the Irish Research Council , St. Vincent’s Foundation and the Irish Cancer Society Collaborative Cancer Research Centre , and BREAST-PREDICT grant CCRC13GAL ( http://www.breastpredict.com ). E.G. is supported by a research grant from Science Foundation Ireland (SFI) under grant number 15/IA/3104 . D.H. was supported by a postdoctoral fellowship from the Fondation pour la Recherche Médicale ( SPF20150934266 ).

Keywords

AEBP2
C10ORF12
EZH2
H3K27me2
H3K27me3
LCOR
PALI1
polycomb
PRC2

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

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

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Conway, E., Jerman, E., Healy, E., Ito, S., Holoch, D., Oliviero, G., Deevy, O., Glancy, E., Fitzpatrick, D. J., Mucha, M., Watson, A., Rice, A. M., Chammas, P., Huang, C., Pratt-Kelly, I., Koseki, Y., Nakayama, M., Ishikura, T., Streubel, G., ... Bracken, A. P. (2018). A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities. Molecular Cell, 70(3), 408-421.e8. https://doi.org/10.1016/j.molcel.2018.03.005

Conway, E, Jerman, E, Healy, E, Ito, S, Holoch, D, Oliviero, G, Deevy, O, Glancy, E, Fitzpatrick, DJ, Mucha, M, Watson, A, Rice, AM, Chammas, P, Huang, C, Pratt-Kelly, I, Koseki, Y, Nakayama, M, Ishikura, T, Streubel, G, Wynne, K, Hokamp, K, McLysaght, A, Ciferri, C, Di Croce, L, Cagney, G, Margueron, R, Koseki, H & Bracken, AP 2018, 'A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities', Molecular Cell, vol. 70, no. 3, pp. 408-421.e8. https://doi.org/10.1016/j.molcel.2018.03.005

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abstract = "The polycomb repressive complex 2 (PRC2) consists of core subunits SUZ12, EED, RBBP4/7, and EZH1/2 and is responsible for mono-, di-, and tri-methylation of lysine 27 on histone H3. Whereas two distinct forms exist, PRC2.1 (containing one polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2), little is known about their differential functions. Here, we report the discovery of a family of vertebrate-specific PRC2.1 proteins, “PRC2 associated LCOR isoform 1” (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and in vivo and is essential for mouse development. Pali1 and Aebp2 define mutually exclusive, antagonistic PRC2 subtypes that exhibit divergent H3K27-tri-methylation activities. The balance of these PRC2.1/PRC2.2 activities is required for the appropriate regulation of polycomb target genes during differentiation. PALI1/2 potentially link polycombs with transcriptional co-repressors in the regulation of cellular identity during development and in cancer. Pali1 and Pali2 form a new family of vertebrate-specific proteins that bind PRC2. Conway et al. show that Pali1 promotes PRC2 methyltransferase activity and defines a distinct PRC2.1 subtype essential for mouse development. They also establish that the balance of PRC2.1 and PRC2.2 activities is essential for proper regulation of polycomb target genes.",

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AU - Healy, Evan

AU - Ito, Shinsuke

AU - Holoch, Daniel

AU - Oliviero, Giorgio

AU - Deevy, Orla

AU - Glancy, Eleanor

AU - Fitzpatrick, Darren J.

AU - Mucha, Marlena

AU - Watson, Ariane

AU - Rice, Alan M.

AU - Chammas, Paul

AU - Huang, Christine

AU - Pratt-Kelly, Indigo

AU - Koseki, Yoko

AU - Nakayama, Manabu

AU - Ishikura, Tomoyuki

AU - Streubel, Gundula

AU - Wynne, Kieran

AU - Hokamp, Karsten

AU - McLysaght, Aoife

AU - Ciferri, Claudio

AU - Di Croce, Luciano

AU - Cagney, Gerard

AU - Margueron, Raphaël

AU - Koseki, Haruhiko

AU - Bracken, Adrian P.

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ER -

A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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