Abstract
Polycomb group (PcG) complexes regulate cellular identity through epigenetic programming of chromatin. Here, we show that SSX2, a germline-specific protein ectopically expressed in melanoma and other types of human cancers, is a chromatin-associated protein that antagonizes BMI1 and EZH2 PcG body formation and derepresses PcG target genes. SSX2 further negatively regulates the level of the PcG-associated histone mark H3K27me3 in melanoma cells, and there is a clear inverse correlation between SSX2/3 expression and H3K27me3 in spermatogenesis. However, SSX2 does not affect the overall composition and stability of PcG complexes, and there is no direct concordance between SSX2 and BMI1/H3K27me3 presence at regulated genes. This suggests that SSX2 antagonizes PcG function through an indirect mechanism, such as modulation of chromatin structure. SSX2 binds double-stranded DNA in a sequence non-specific manner in agreement with the observed widespread association with chromatin. Our results implicate SSX2 in regulation of chromatin structure and function.
Highlights
Polycomb group (PcG) proteins are negative regulators of gene expression essential for the maintenance of important biological processes such as cell identity, stem cell self-renewal and cell cycle regulation [1]
To investigate the role of wild-type SSX2 in the regulation of PcG protein function, we expressed the protein in SSXnegative cancer cell lines derived from tumor types that frequently express SSX2 [39,42,43,44], including melanoma (A375; DOX inducible model), breast cancer (MCF7; DOX inducible model), colon cancer (HCT116) and tumorigenic mesenchymal stem cells (hMSC-TERT20; sarcomas may be derived from transformed hMSC [45])
PcG proteins can be found in nuclear concentrations called PcG bodies, which may vary in size and number among different types of cells [46], and these structures appear to be important for PcG function
Summary
Polycomb group (PcG) proteins are negative regulators of gene expression essential for the maintenance of important biological processes such as cell identity, stem cell self-renewal and cell cycle regulation [1]. PRC2 consists of the core subunits EED, EZH2 and SUZ12 and catalyzes tri-methylation of histone H3 at lysine 27 (H3K27me). PRC2 consists of the core subunits EED, EZH2 and SUZ12 and catalyzes tri-methylation of histone H3 at lysine 27 (H3K27me3) This modification serves as a platform for chromatin binding of PRC1, whereby the essential subunits BMI1 and RING1A/B promote mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub). The H2AK119ub modifications are highly abundant and aid chromatin compaction [3] This model of ordered recruitment plays an essential role in PcG protein function, partial uncoupling of PcG proteins and H3K27me, as shown by chromatin immunoprecipitation (ChIP) experiments, and different phenotypic effects caused by perturbing individual PcG members, suggest a highly complex function of these proteins [4]. Context-specific interactions with proteins and RNA molecules may increase the complexity of PcG protein function
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