SSX2 is a novel DNA-binding protein that antagonizes polycomb group body formation and gene repression

• Published in: Nucleic acids research 2014-10, Vol.42 (18), p.11433-11446
• Main Authors: Gjerstorff, Morten Frier, Relster, Mette Marie, Greve, Katrine Buch Viden, Moeller, Jesper Bonnet, Elias, Daniel, Lindgreen, Jonas Nørrelund, Schmidt, Steffen, Mollenhauer, Jan, Voldborg, Bjørn, Pedersen, Christina Bøg, Brückmann, Nadine Heidi, Møllegaard, Niels Erik, Ditzel, Henrik Jørn
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Nucleus - metabolism; Chromatin - metabolism; DNA - chemistry; DNA - metabolism; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Gene regulation, Chromatin and Epigenetics; Histones - metabolism; Humans; Melanoma - genetics; Melanoma - metabolism; Neoplasm Proteins - metabolism; Neoplasm Proteins - physiology; Polycomb Repressive Complex 1 - antagonists & inhibitors; Polycomb Repressive Complex 1 - chemistry; Polycomb Repressive Complex 1 - metabolism; Polycomb Repressive Complex 2 - antagonists & inhibitors; Polycomb Repressive Complex 2 - chemistry; Polycomb Repressive Complex 2 - metabolism; Polycomb-Group Proteins - antagonists & inhibitors; Repressor Proteins - metabolism; Repressor Proteins - physiology; Spermatogenesis
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gku852

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.