An AUTS2-Polycomb complex activates gene expression in the CNS.
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.
Mesh Terms:
Animals, Behavior, Animal, Cell Cycle Proteins, Central Nervous System, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Knockout Techniques, Genotype, HEK293 Cells, Histones, Humans, Male, Mice, Mice, Inbred C57BL, Phosphorylation, Proteins, Ubiquitination
Animals, Behavior, Animal, Cell Cycle Proteins, Central Nervous System, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Knockout Techniques, Genotype, HEK293 Cells, Histones, Humans, Male, Mice, Mice, Inbred C57BL, Phosphorylation, Proteins, Ubiquitination
Nature
Date: Dec. 18, 2014
PubMed ID: 25519132
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