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

Sudarshan, D.; Avvakumov, N.; Lalonde, M.-E.; Alerasool, N.; Jacquet, K.; Mameri, A.; Rousseau, J.; Lambert, J.-P.; Paquet, E.; Setty, S. T.; Loehr, J.; Gingras, A.-C.; Coulombe, B.; Taipale, M.; Doyon, Y.; Cote, J.

doi:10.1101/2021.03.26.436670

bioRxiv · 10.1101/2021.03.26.436670

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

Sudarshan, D.·Avvakumov, N.·Lalonde, M.-E.·Alerasool, N.·Jacquet, K.·Mameri, A.·Rousseau, J.·Lambert, J.-P.·Paquet, E.·Setty, S. T.·Loehr, J.·Gingras, A.-C.·Coulombe, B.·Taipale, M.·Doyon, Y.·Cote, J.

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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, 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 ESS, JAZF1-SUZ12, is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating similar outcomes as 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 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.

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Sudarshan, D., Avvakumov, N., Lalonde, M.-E., Alerasool, N., Jacquet, K., Mameri, A., Rousseau, J., Lambert, J.-P., Paquet, E., Setty, S. T., Loehr, J., Gingras, A.-C., Coulombe, B., Taipale, M., Doyon, Y., Cote, J.. 2021-03-26. Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci. https://doi.org/10.1101/2021.03.26.436670

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