Journal
NATURE
Volume 516, Issue 7531, Pages 349-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13921
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Funding
- National Institute of Health [GM-64844]
- Simons Foundation Autism Research Initiative (SFARI)
- NIH [1DP2MH100012-01, 5T32CA160002, 1F32GM105275, F32AA022842]
- Seaver Autism Foundation
- Brain and Behavioral Research Fund [18194]
- SFARI
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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.
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