title: An AUTS2-Polycomb complex activates gene expression in the CNS.
abstract: Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
authors.affiliation: Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Lee
authors.affiliation: Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Stafford
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: von Schimmelmann
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Schaefer
authors.affiliation: Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D055786:Gene Knockout Techniques; D005838:Genotype; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D054875:Ubiquitination
chemical_list: C554283:AUTS2 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D006657:Histones; C116662:PRC1 protein, human; D011506:Proteins; D014157:Transcription Factors