Recurrent chromosomal translocations in sarcomas create a mega-complex 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 (ESS) and Ossifying FibroMyxoid Tumors (OFMT) leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a co-activator 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 mega-complex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome. These are linked to aberrant gene expression, in particular over an entire topologically-associated domain including part of the HOXD cluster. Furthermore, we show that JAZF1, implicated with PRC2 components in the most frequent translocations in ESS, is a potent transcription activator that physically associates with NuA4/TIP60. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas employ 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. HighlightsO_LIRecurrent oncogenic chromosomal translocations fuse Polycomb-like-1 (PHF1) with different subunits of the NuA4/TIP60 complex C_LIO_LITranslocation produces a mega-complex containing NuA4/TIP60 and PRC2 activities C_LIO_LITranslocation leads to mistargeting of histone marks throughout the genome and changes in gene expression C_LIO_LILoss of H3K27me3 and gain of H4ac on HOXD cluster are restricted to a topologically-associated domain (TAD) C_LIO_LIA highly recurrent JAZF1-SUZ12 translocation uses the same mechanism merging NuA4/TIP60 with PRC2 C_LI