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

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.

Source: Genes and Development - July 14, 2022 Category: Genetics & Stem Cells Authors: Sudarshan, D., Avvakumov, N., Lalonde, M.-E., Alerasool, N., Joly-Beauparlant, C., Jacquet, K., Mameri, A., Lambert, J.-P., Rousseau, J., Lachance, C., Paquet, E., Herrmann, L., Thonta Setty, S., Loehr, J., Bernardini, M. Q., Rouzbahman, M., Gingras, A.-C Tags: Research Papers Source Type: research