Department of Molecular Genomics. Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
Vall d'Hebron Institute of Research (VHIR), Passeig de la Vall d'Hebron, 119; E-08035 Barcelona, Spain. Institut Català per la Recerca i Estudis Avançats (ICREA), Barcelona 08018, Spain.
Nucleic Acids Res. 2018 Apr 20;46(7):3351-3365. doi: 10.1093/nar/gky093.
During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFβ signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis-regulatory regions, we use CRISPR-Cas9 technology to demonstrate that the TGFβ-responsive Neurog2 enhancer is essential for proper neuronal polarization.
在神经发生过程中，动态发育线索、转录因子和组蛋白修饰酶通过调节神经特异性增强子的活性来调节基因表达程序。短暂的发育信号如何协调转录因子募集到增强子上，以及组蛋白修饰因子在多大程度上有助于增强子活性，这些问题开始被揭示。在这里，我们利用神经干细胞作为模型，揭示了 TGFβ信号响应中神经增强子激活的机制。全基因组实验表明，神经前体细胞因子 ASCL1 协助 SMAD3 结合增强子的一部分。一旦位于增强子上，SMAD3 就会招募组蛋白去甲基酶 JMJD3 和重塑因子 CHD8，为增强子转录和后续基因激活创造适当的染色质景观。最后，为了分析顺式调控区域所带来的表型特征，我们使用 CRISPR-Cas9 技术证明 TGFβ 反应性 Neurog2 增强子对于正确的神经元极化是必不可少的。
