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. Polycomb group proteins are known to maintain gene repression during development; however, when autism susceptibility candidate 2 (AUTS2) associates with some Polycomb group complexes, these complexes have an unexpected gene activation role, offering new insight into the role of AUTS2 in neurological disorders. The role of AUTS2 in neurological disorders Polycomb group proteins, which maintain gene repression during development, comprise two main complexes (PRC1 and PRC2), with distinct enzymatic activities. Some PRC1 complexes associate with autism susceptibility candidate 2 (AUTS2), the gene for which is often disrupted in neuronal disorders. Here, Danny Reinberg and colleagues find that AUTS2 confers an unexpected transcriptional activation function on PRC1, and the PRC1–AUTS2 complex regulates neuronal genes. Deletion of the Auts2 locus in the mouse central nervous system leads to developmental defects. AUTS2 may have a key role in modulating PRC1 activity during normal brain development.