Open AccessRecurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci
Author(s) -
Deepthi Sudarshan,
Nikita Avvakumov,
Marie-Eve Lalonde,
Nader Alerasool,
Charles Joly-Beauparlant,
Karine Jacquet,
Amel Mameri,
JeanPhilippe Lambert,
Justine Rousseau,
Catherine Lachance,
Éric R. Paquet,
Lara Herrmann,
Samarth Thonta Setty,
Jérémy Loehr,
Marcus Q. Bernardini,
Marjan Rouzbahman,
AnneClaude Gingras,
Benoit Coulombe,
Arnaud Droit,
Mikko Taipale,
Yannick Doyon,
Jacques Côté
Publication year - 2022
Publication title -
genes and development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.136
H-Index - 438
eISSN - 1549-5477
pISSN - 0890-9369
DOI - 10.1101/gad.348982.121
Subject(s) - biology , prc2 , chromosomal translocation , chromatin , polycomb group proteins , histone h3 , ezh2 , histone , microbiology and biotechnology , genetics , cancer research , transcription factor , gene , repressor
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.