title: SSX2 is a novel DNA-binding protein that antagonizes polycomb group body formation and gene repression.
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.
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark mgjerstorff@health.sdu.dk.
authors.forename: Morten Frier
authors.initials: MF
authors.lastname: Gjerstorff
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Mette Marie
authors.initials: MM
authors.lastname: Relster
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Katrine Buch Viden
authors.initials: KB
authors.lastname: Greve
authors.affiliation: Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Jesper Bonnet
authors.initials: JB
authors.lastname: Moeller
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Daniel
authors.initials: D
authors.lastname: Elias
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Jonas Nørrelund
authors.initials: JN
authors.lastname: Lindgreen
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark The Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark The Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.affiliation: The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Voldborg
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Christina Bøg
authors.initials: CB
authors.lastname: Pedersen
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark.
authors.forename: Nadine Heidi
authors.initials: NH
authors.lastname: Brückmann
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200, Denmark.
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Møllegaard
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, DK-5000, Denmark The Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, Odense, DK-5000, Denmark Department of Oncology, Odense University Hospital, Odense, DK-5000, Denmark.
authors.forename: Henrik Jørn
authors.initials: HJ
authors.lastname: Ditzel
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000502:physiology; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D013091:Spermatogenesis
chemical_list: C069077:BMI1 protein, human; D002843:Chromatin; D006657:Histones; D009363:Neoplasm Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C093962:synovial sarcoma X breakpoint proteins; D004247:DNA; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1