Catacomb: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism

Andrea Piunti, Edwin Smith, Marc Alard Morgan, Michal Ugarenko, Natalia Khaltyan, Kathryn A. Helmin, Caila A. Ryan, David C. Murray, Ryan A. Rickels, Bahar D. Yilmaz, Emily J. Rendleman, Jeffrey Nicholas Savas, Benjamin Singer, Serdar E Bulun, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67’s interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: CATACOMB (catalytic antagonist of Polycomb; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As CATACOMB expression is regulated through DNA methylation/ demethylation, we propose CATACOMB as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.

Original languageEnglish (US)
Article numbereaax2887
JournalScience Advances
Volume5
Issue number7
DOIs
StatePublished - Jan 1 2019

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methionine
methylation
genes
deoxyribonucleic acid
COMPASS (programming language)
mutations
amino acids
grade
fusion
cancer
proteins
interactions

ASJC Scopus subject areas

  • General
  • Physics and Astronomy (miscellaneous)

Cite this

Piunti, Andrea ; Smith, Edwin ; Morgan, Marc Alard ; Ugarenko, Michal ; Khaltyan, Natalia ; Helmin, Kathryn A. ; Ryan, Caila A. ; Murray, David C. ; Rickels, Ryan A. ; Yilmaz, Bahar D. ; Rendleman, Emily J. ; Savas, Jeffrey Nicholas ; Singer, Benjamin ; Bulun, Serdar E ; Shilatifard, Ali. / Catacomb : An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism. In: Science Advances. 2019 ; Vol. 5, No. 7.
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abstract = "Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67’s interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: CATACOMB (catalytic antagonist of Polycomb; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As CATACOMB expression is regulated through DNA methylation/ demethylation, we propose CATACOMB as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.",
author = "Andrea Piunti and Edwin Smith and Morgan, {Marc Alard} and Michal Ugarenko and Natalia Khaltyan and Helmin, {Kathryn A.} and Ryan, {Caila A.} and Murray, {David C.} and Rickels, {Ryan A.} and Yilmaz, {Bahar D.} and Rendleman, {Emily J.} and Savas, {Jeffrey Nicholas} and Benjamin Singer and Bulun, {Serdar E} and Ali Shilatifard",
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Catacomb : An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism. / Piunti, Andrea; Smith, Edwin; Morgan, Marc Alard; Ugarenko, Michal; Khaltyan, Natalia; Helmin, Kathryn A.; Ryan, Caila A.; Murray, David C.; Rickels, Ryan A.; Yilmaz, Bahar D.; Rendleman, Emily J.; Savas, Jeffrey Nicholas; Singer, Benjamin; Bulun, Serdar E; Shilatifard, Ali.

In: Science Advances, Vol. 5, No. 7, eaax2887, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Catacomb

T2 - An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism

AU - Piunti, Andrea

AU - Smith, Edwin

AU - Morgan, Marc Alard

AU - Ugarenko, Michal

AU - Khaltyan, Natalia

AU - Helmin, Kathryn A.

AU - Ryan, Caila A.

AU - Murray, David C.

AU - Rickels, Ryan A.

AU - Yilmaz, Bahar D.

AU - Rendleman, Emily J.

AU - Savas, Jeffrey Nicholas

AU - Singer, Benjamin

AU - Bulun, Serdar E

AU - Shilatifard, Ali

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67’s interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: CATACOMB (catalytic antagonist of Polycomb; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As CATACOMB expression is regulated through DNA methylation/ demethylation, we propose CATACOMB as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.

AB - Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67’s interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: CATACOMB (catalytic antagonist of Polycomb; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As CATACOMB expression is regulated through DNA methylation/ demethylation, we propose CATACOMB as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.

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U2 - 10.1126/sciadv.aax2887

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M3 - Article

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SN - 0019-5596

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