NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program
NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program
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DOI：
10.15252/embj.201591206
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发表时间：
2016-01-01
期刊：
影响因子：
11.4
通讯作者：
Tiwari, Vijay K.
中科院分区：
文献类型：
--
作者：
Pataskar, Abhijeet;Jung, Johannes;Tiwari, Vijay K.
细胞命运特化依赖于在胚胎发育的不同阶段变得可用的关键转录因子的作用。其中一个因子是NeuroD1，它对引发神经元发育程序至关重要，并具有将其他细胞类型重编程为神经元的能力。鉴于这种能力，重要的是要了解它的目标和神经元特化的机制。在这里，我们表明，NeuroD1直接结合神经元基因的调控元件，这些基因在发育过程中被表观遗传机制沉默。这种靶向足以启动赋予转录能力的事件，包括转录因子景观的重编程，异染色质向常染色质的转化以及染色质可及性的增加，表明NeuroD1的潜在先锋因子能力。神经元命运基因的转录诱导通过表观遗传记忆维持，尽管在神经发生期间短暂的NeuroD1诱导。NeuroD1还诱导参与上皮向间充质转化的基因，从而促进神经元迁移。我们的研究不仅揭示了驱动神经发生的NeuroD1依赖性基因调控程序，而且还增加了我们对发育过程中细胞命运规范如何涉及转录因子和表观遗传机制的协调作用的理解。
Cell fate specification relies on the action of critical transcription factors that become available at distinct stages of embryonic development. One such factor is NeuroD1, which is essential for eliciting the neuronal development program and possesses the ability to reprogram other cell types into neurons. Given this capacity, it is important to understand its targets and the mechanism underlying neuronal specification. Here, we show that NeuroD1 directly binds regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms. This targeting is sufficient to initiate events that confer transcriptional competence, including reprogramming of transcription factor landscape, conversion of heterochromatin to euchromatin, and increased chromatin accessibility, indicating potential pioneer factor ability of NeuroD1. The transcriptional induction of neuronal fate genes is maintained via epigenetic memory despite a transient NeuroD1 induction during neurogenesis. NeuroD1 also induces genes involved in the epithelial-to-mesenchymal transition, thereby promoting neuronal migration. Our study not only reveals the NeuroD1-dependent gene regulatory program driving neurogenesis but also increases our understanding of how cell fate specification during development involves a concerted action of transcription factors and epigenetic mechanisms.