Rapid Chromatin Switch in the Direct Reprogramming of Fibroblasts to Neurons.
Rapid Chromatin Switch in the Direct Reprogramming of Fibroblasts to Neurons.
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DOI：
10.1016/j.celrep.2017.09.011
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发表时间：
2017-09-26
期刊：
影响因子：
8.8
通讯作者：
Chang HY
中科院分区：
文献类型：
--
作者：
Wapinski OL;Lee QY;Chen AC;Li R;Corces MR;Ang CE;Treutlein B;Xiang C;Baubet V;Suchy FP;Sankar V;Sim S;Quake SR;Dahmane N;Wernig M;Chang HY
转录因子（TF）如何将一种细胞谱系重编程为另一种细胞谱系仍不清楚。在这里，我们定义染色质可及性的变化，诱导的前神经TF Ascl1在整个转化成纤维细胞诱导神经元（iN）细胞。成千上万的基因组位点早在Ascl 1诱导后12小时就受到影响。令人惊讶的是，超过80%的可访问性变化发生在3周重编程过程的第2天和第5天之间。这种染色质转换与内源性神经元TF的强烈激活和神经元启动子和增强子的核小体定相相相一致。iN细胞随后的形态和功能成熟是在相对较少的染色质重构的情况下完成的。整合染色质可及性和转录组变化，我们建立了iN细胞重编程过程中动态TF调控的网络模型，并确定Zfp238，Sox 8和Dlx 3为Ascl 1下游的关键TF。这些结果揭示了一个单一的，协调的表观基因组开关直接重编程过程中，相反，逐步细胞命运的转变发展。
How transcription factors (TFs) reprogram one cell lineage to another remains unclear. Here, we define chromatin accessibility changes induced by the proneural TF Ascl1 throughout conversion of fibroblasts into induced neuronal (iN) cells. Thousands of genomic loci are affected as early as 12 hours after Ascl1 induction. Surprisingly, over 80% of the accessibility changes occur between days 2 and 5 of the 3-week reprogramming process. This chromatin switch coincides with robust activation of endogenous neuronal TFs and nucleosome phasing of neuronal promoters and enhancers. Subsequent morphological and functional maturation of iN cells are accomplished with relatively little chromatin reconfiguration. Integrating chromatin accessibility and transcriptome changes, we built a network model of dynamic TF regulation during iN cell reprogramming, and identified Zfp238, Sox8 and Dlx3 as key TFs downstream of Ascl1. These results reveal a singular, coordinated epigenomic switch during direct reprogramming, in contrast to step-wise cell fate transitions in development.
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单细胞染色质可及性揭示了调节变化的原理。
影响因子：
64.8
作者：
Buenrostro JD;Wu B;Litzenburger UM;Ruff D;Gonzales ML;Snyder MP;Chang HY;Greenleaf WJ
通讯作者：
Greenleaf WJ