Deciphering the conserved dynamic transcriptional signature and regulatory software governing neuronal fate commitment

The transcriptional program underlying neuronal apoptosis and survival has to date been partially characterized. However, the complete spectrum of genes/proteins as well as the ‘regulatory software’ controlling neuronal fate decisions remain almost entirely unknown. Here, for the first time, we characterized the earliest molecular events following the induction of neuronal apoptosis and its rescue by three potent anti-apoptotic growth factors (GFs), in order to identify key genes and upstream regulators primarily responsible for driving execution of these processes. A core set of 175 survival-related genes (SRGs) with opposite transcriptional signatures between apoptosis and GF-mediated survival was identified. Promoter motif analysis of SRGs revealed a repertoire of intrinsic upstream regulators that may drive the apoptotic/survival switch, with Hoxd9 predicted to be the master regulator. Finally, the clinical implication of SRGs in the pathogenesis of neurological and neuropsychiatric diseases, here emerged, suggested their potential utility as targets for treating these severe disorders.迄今为止，神经元细胞凋亡与存活相关的转录调控程序仅得到了部分解析。然而，调控神经元命运抉择的完整基因/蛋白谱以及其‘调控软件’仍几乎完全未知。本研究首次对神经元凋亡诱导后最早发生的分子事件，以及三种强效抗凋亡生长因子（growth factors, GFs）介导的神经元存活挽救过程进行了系统表征，旨在鉴定驱动这两类过程的关键基因与上游调控因子。研究鉴定得到了175个存活相关基因（survival-related genes, SRGs）的核心集合，这些基因在细胞凋亡与GF介导的存活状态下呈现相反的转录特征。对SRGs的启动子基序分析揭示了一系列可能介导凋亡/存活转换的内源性上游调控因子，其中Hoxd9被预测为核心主调控因子。最后，本研究揭示的SRGs在神经及神经精神疾病发病机制中的临床关联，提示其可作为治疗此类重症疾病的潜在药物靶点。