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 (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.
Highlights
Recurrent oncogenic chromosomal translocations fuse Polycomb-like-1 (PHF1) with different subunits of the NuA4/TIP60 complex
Translocation produces a mega-complex containing NuA4/TIP60 and PRC2 activities
Translocation leads to mistargeting of histone marks throughout the genome and changes in gene expression
Loss of H3K27me3 and gain of H4ac on HOXD cluster are restricted to a topologically-associated domain (TAD)
A highly recurrent JAZF1-SUZ12 translocation uses the same mechanism merging NuA4/TIP60 with PRC2
Competing Interest Statement
The authors have declared no competing interest.