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Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci

Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame...

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Autores principales: Sudarshan, Deepthi, Avvakumov, Nikita, Lalonde, Marie-Eve, Alerasool, Nader, Joly-Beauparlant, Charles, Jacquet, Karine, Mameri, Amel, Lambert, Jean-Philippe, Rousseau, Justine, Lachance, Catherine, Paquet, Eric, Herrmann, Lara, Thonta Setty, Samarth, Loehr, Jeremy, Bernardini, Marcus Q., Rouzbahman, Marjan, Gingras, Anne-Claude, Coulombe, Benoit, Droit, Arnaud, Taipale, Mikko, Doyon, Yannick, Côté, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296003/
https://www.ncbi.nlm.nih.gov/pubmed/35710139
http://dx.doi.org/10.1101/gad.348982.121
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author Sudarshan, Deepthi
Avvakumov, Nikita
Lalonde, Marie-Eve
Alerasool, Nader
Joly-Beauparlant, Charles
Jacquet, Karine
Mameri, Amel
Lambert, Jean-Philippe
Rousseau, Justine
Lachance, Catherine
Paquet, Eric
Herrmann, Lara
Thonta Setty, Samarth
Loehr, Jeremy
Bernardini, Marcus Q.
Rouzbahman, Marjan
Gingras, Anne-Claude
Coulombe, Benoit
Droit, Arnaud
Taipale, Mikko
Doyon, Yannick
Côté, Jacques
author_facet Sudarshan, Deepthi
Avvakumov, Nikita
Lalonde, Marie-Eve
Alerasool, Nader
Joly-Beauparlant, Charles
Jacquet, Karine
Mameri, Amel
Lambert, Jean-Philippe
Rousseau, Justine
Lachance, Catherine
Paquet, Eric
Herrmann, Lara
Thonta Setty, Samarth
Loehr, Jeremy
Bernardini, Marcus Q.
Rouzbahman, Marjan
Gingras, Anne-Claude
Coulombe, Benoit
Droit, Arnaud
Taipale, Mikko
Doyon, Yannick
Côté, Jacques
author_sort Sudarshan, Deepthi
collection PubMed
description Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a coactivator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a megacomplex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically associating domain including part of the HOXD cluster. This is linked to aberrant gene expression—most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1—implicated with a PRC2 component in the most frequent translocation in ESSs, JAZF1-SUZ12—is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating outcomes similar to those of EPC1-PHF1. Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas use the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes, leading to mislocalization of histone marks and aberrant Polycomb target gene expression.
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spelling pubmed-92960032022-12-01 Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci Sudarshan, Deepthi Avvakumov, Nikita Lalonde, Marie-Eve Alerasool, Nader Joly-Beauparlant, Charles Jacquet, Karine Mameri, Amel Lambert, Jean-Philippe Rousseau, Justine Lachance, Catherine Paquet, Eric Herrmann, Lara Thonta Setty, Samarth Loehr, Jeremy Bernardini, Marcus Q. Rouzbahman, Marjan Gingras, Anne-Claude Coulombe, Benoit Droit, Arnaud Taipale, Mikko Doyon, Yannick Côté, Jacques Genes Dev Research Paper Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a coactivator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a megacomplex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically associating domain including part of the HOXD cluster. This is linked to aberrant gene expression—most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1—implicated with a PRC2 component in the most frequent translocation in ESSs, JAZF1-SUZ12—is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating outcomes similar to those of EPC1-PHF1. Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas use the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes, leading to mislocalization of histone marks and aberrant Polycomb target gene expression. Cold Spring Harbor Laboratory Press 2022-06-01 /pmc/articles/PMC9296003/ /pubmed/35710139 http://dx.doi.org/10.1101/gad.348982.121 Text en © 2022 Sudarshan et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research Paper
Sudarshan, Deepthi
Avvakumov, Nikita
Lalonde, Marie-Eve
Alerasool, Nader
Joly-Beauparlant, Charles
Jacquet, Karine
Mameri, Amel
Lambert, Jean-Philippe
Rousseau, Justine
Lachance, Catherine
Paquet, Eric
Herrmann, Lara
Thonta Setty, Samarth
Loehr, Jeremy
Bernardini, Marcus Q.
Rouzbahman, Marjan
Gingras, Anne-Claude
Coulombe, Benoit
Droit, Arnaud
Taipale, Mikko
Doyon, Yannick
Côté, Jacques
Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci
title Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci
title_full Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci
title_fullStr Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci
title_full_unstemmed Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci
title_short Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci
title_sort recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes nua4/tip60 to polycomb target loci
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296003/
https://www.ncbi.nlm.nih.gov/pubmed/35710139
http://dx.doi.org/10.1101/gad.348982.121
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