AUTS2 confers transcriptional activation to PRC1 in the CNS (RNA-Seq)

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). While AUTS2 is often disrupted in patients with neuronal disorders, the underlying mechanism 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 thwarts PRC1 repressive activity and AUTS2-mediated recruitment of P300 leads to gene activation. ChIP-seq of AUTS2 shows that it regulates neuronal gene expression through promoter association. Conditional CNS targeting of Auts2 in a mouse model leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases. mRNA profiles of P1 brain from wild type mice were generated by deep sequencing天然存在的多梳抑制复合体1（Polycomb Repressive Complex 1, PRC1）变异体由多梳家族蛋白核心组装体与附加因子构成，其中令人意外的是包含自闭症易感候选因子2（Autism Susceptibility Candidate 2, AUTS2）。尽管AUTS2在神经系统疾病患者中常发生功能紊乱，但其背后的分子机制仍不明确。本研究针对此前已鉴定的PRC1复合体（PRC1-AUTS2）中AUTS2的功能，以及其在神经发育背景下的作用展开了探究。与PRC1经典的基因沉默功能相悖，PRC1-AUTS2可激活转录过程。生化实验证实，PRC1-AUTS2中的酪蛋白激酶2（Casein Kinase 2, CK2）组分可拮抗PRC1的沉默活性，而AUTS2介导的组蛋白乙酰转移酶P300（P300）招募则介导了基因激活。针对AUTS2的染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）结果显示，其可通过启动子结合调控神经元基因的表达。在小鼠模型中对Auts2进行条件性中枢神经系统（Central Nervous System, CNS）靶向操作，会引发多种发育缺陷。上述研究结果揭示了一种天然的PRC1活性调控途径，将关键表观遗传调控因子与神经元功能及疾病建立了关联。本研究通过深度测序获取了野生型小鼠P1期脑组织的mRNA表达谱。