Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA.
Friedman Brain Institute, Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
Nature. 2014 Dec 18;516(7531):349-54. doi: 10.1038/nature13921.
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.
多梳抑制复合物 1 (PRC1) 的自然变异包含多梳组蛋白的核心组件和其他因子，其中令人惊讶的是包括自闭症易感性候选基因 2 (AUTS2)。尽管 AUTS2 经常在神经元疾病患者中被破坏，但发病机制尚不清楚。我们研究了 AUTS2 作为先前鉴定的 PRC1 复合物 (PRC1-AUTS2) 的一部分的作用，以及在神经发育中的作用。与 PRC1 在基因抑制中的典型作用相反，PRC1-AUTS2 激活转录。生化研究表明，PRC1-AUTS2 的 CK2 成分中和了 PRC1 的抑制活性，而 AUTS2 介导的 P300 募集导致基因激活。染色质免疫沉淀测序 (ChIP-seq) 表明，AUTS2 通过启动子关联调节神经元基因表达。条件性靶向 Auts2 在小鼠中枢神经系统 (CNS) 中导致各种发育缺陷。这些发现揭示了一种自然的方式来颠覆 PRC1 的活性，将关键的表观遗传调节剂与神经元功能和疾病联系起来。
