Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis.
Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis.
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DOI：
10.1016/j.celrep.2015.02.025
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发表时间：
2015-03-10
期刊：
影响因子：
8.8
通讯作者：
Castro DS
中科院分区：
文献类型：
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作者：
Raposo AASF;Vasconcelos FF;Drechsel D;Marie C;Johnston C;Dolle D;Bithell A;Gillotin S;van den Berg DLC;Ettwiller L;Flicek P;Crawford GE;Parras CM;Berninger B;Buckley NJ;Guillemot F;Castro DS
原神经转录因子Ascl1协调沿着神经元谱系的增殖和分化祖细胞的基因表达。在这里，我们使用神经发生的细胞模型来研究Ascl1如何与染色质景观相互作用，以调节促进神经元分化时的基因表达。我们发现Ascl1结合主要发生在远端增强子上，并与基因转录的激活有关。令人惊讶的是，Ascl1在神经干细胞/祖细胞中与其结合部位的可及性在分化过程中基本保持不变，因为Ascl1针对的是增殖细胞中容易获得和关闭的染色质区域。此外，Ascl1的结合通常先于染色质可及性的增加和开放染色质新区域的出现，这与分化过程中从头基因的表达有关。我们的结果揭示了Ascl1在神经发生过程中促进染色质可及性的功能，将Ascl1靶区的染色质景观与其转录程序的时间进程联系起来。Ascl1的全基因组结合与转录激活相关，Ascl1可与增殖细胞的开放染色质和闭合染色质结合，促进其靶部位染色质的局部可及性，Ascl1位点的染色质动态调节其程序的时间进程，神经转录因子Ascl1在神经发生过程中依次激活增殖和分化祖细胞的靶基因。在这里，Raposo等人。显示Ascl1与增殖细胞中封闭和开放的染色质结合。与封闭染色质的结合促进了分化特异性基因的可及性和激活。因此，Ascl1靶区染色质景观的动态调节了Ascl1靶点的时间起始。
The proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program. Genome-wide binding of Ascl1 correlates with transcription activation Ascl1 can bind to both open and closed chromatin in proliferating cells Ascl1 promotes local chromatin accessibility at its target sites Chromatin dynamics at Ascl1 sites regulates temporal progression of its program The proneural transcription factor Ascl1 sequentially activates target genes in proliferating and differentiating progenitors during neurogenesis. Here Raposo et al. show that Ascl1 binds closed and open chromatin in proliferating cells. Binding to closed chromatin promotes accessibility and activation of differentiation specific genes. Thus, dynamics of chromatin landscape at Ascl1 target regions regulate the temporal onset of Ascl1 targets.