Activating transcription factors Atf3/Atf4 drive early molecular events preceding neural stem cell differentiation and control neuron formation [Short]. Activating transcription factors Atf3/Atf4 drive early molecular events preceding neural stem cell differentiation and control neuron formation [Short]

The generation of new neurons from neural stem cells is tightly controlled by transcriptional programs. To induce cell fate switches that establish neuronal identities, differentiating neural precursor cells (NPCs) must undergo rapid and dynamic gene expression changes. However, the neuronal fate-determining molecular events that precede NPC differentiation are incompletely understood. Using high temporal resolution transcriptional profiling of adult hippocampal NPC differentiation, we here identified the activating transcription factors Atf3 and Atf4 as early switch regulators that drive NPC fate and control neuron formation. We found that Atf3/4 are rapidly upregulated in NPCs upon induction of differentiation and drive dynamic gene expression changes associated with neurogenesis. Pharmacological and genetic perturbation of Atf4 demonstrated its importance for neuron formation. Sustained overexpression of Atf3 hampered neurogenesis by repressing long non-coding RNA Miat. Our results demonstrate the critical role of an Atf3/Atf4-controlled transcriptional network in driving early molecular events during neurogenesis. Overall design: 17 samples from different timepoints after onset of differentiation

神经干细胞生成新生神经元的过程，受到转录程序的严密调控。为诱导确立神经元身份的细胞命运转换，正在分化的神经前体细胞（Neural Precursor Cells，NPCs）必须经历快速且动态的基因表达变化。然而，神经前体细胞分化前决定神经元命运的分子事件尚未被完全阐明。本研究通过对成年海马神经前体细胞分化开展高时间分辨率转录谱分析，鉴定出激活型转录因子Atf3与Atf4作为早期命运转换调控因子，可调控神经前体细胞命运并控制神经元生成。研究发现，在分化诱导后，Atf3与Atf4会在神经前体细胞中快速上调，并驱动与神经发生相关的动态基因表达变化。通过对Atf4进行药理学与遗传学扰动实验，证实了其在神经元生成过程中的重要作用。持续过表达Atf3会通过抑制长链非编码RNA Miat，阻碍神经发生进程。本研究结果表明，由Atf3/Atf4调控的转录网络在驱动神经发生早期分子事件中发挥关键作用。实验整体设计：采集分化启动后不同时间点的17份样本。