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

Deepthi Sudarshan1, Nikita Avvakumov1,9, Marie-Eve Lalonde1,9, Nader Alerasool2,10, Charles Joly-Beauparlant3,10, Karine Jacquet1,10, Amel Mameri1,10, Jean-Philippe Lambert1,4, Justine Rousseau5, Catherine Lachance1, Eric Paquet1, Lara Herrmann3, Samarth Thonta Setty3, Jeremy Loehr1, Marcus Q. Bernardini6,7, Marjan Rouzbahman8, Anne-Claude Gingras4, Benoit Coulombe5, Arnaud Droit3, Mikko Taipale2, Yannick Doyon1 and Jacques Côté1 1Centre Hospitalier Universitaire (CHU) de Québec-Université Laval Research Center, Laval University Cancer Research Center, Québec City, Québec G1R 3S3, Canada; 2Donnelly Centre for Cellular and Biomolecular Research, Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; 3Computational Biology Laboratory, CHU de Québec-Université Laval Research Center, Québec City, Québec G1V 4G2, Canada; 4Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; 5Institut de Recherches Cliniques de Montréal, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada; 6Department of Gynecologic Oncology, Princess Margaret Cancer Center, University Health Network, Sinai Health System, Toronto, Ontario M5B 2M9, Canada; 7Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5G 1X8, Canada; 8Department of Laboratory Medicine and Pathobiology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario M5G 2C4, Canada Corresponding authors: jacques.cotecrhdq.ulaval.ca, yannick.doyoncrchudequebec.ulaval.ca

9 These authors contributed equally to this work.

10 These authors contributed equally to this work.

Abstract

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.

Received August 31, 2021. Accepted May 31, 2022.

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