Snail regulates MyoD binding-site occupancy to direct enhancer switching and differentiation-specific transcription in myogenesis.
Snail regulates MyoD binding-site occupancy to direct enhancer switching and differentiation-specific transcription in myogenesis.
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DOI：
10.1016/j.molcel.2012.05.046
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发表时间：
2012-08-10
期刊：
影响因子：
16
通讯作者：
Rudnicki MA
中科院分区：
文献类型：
--
作者：
Soleimani VD;Yin H;Jahani-Asl A;Ming H;Kockx CE;van Ijcken WF;Grosveld F;Rudnicki MA
在骨骼肌发生过程中，转录因子MyoD在祖细胞中激活的转录程序与末梢分化细胞不同。通过ChIP-Seq和基因表达分析，我们发现在原代成肌细胞中，Snail-HDAC1/2抑制复合物结合并将MyoD排除在其靶标之外。值得注意的是，Snail结合了富含G/C中心二核苷酸的E box基序，这些位点几乎完全与分化过程中表达的基因相关。相比之下，Snail不结合肌母细胞中与MyoD靶点相关的富含A/ t的E盒子。因此，Snai1-HDAC1/2阻止MyoD占据分化特异性调控元件，并且从Snail到MyoD结合的变化通常导致分化过程中增强子的切换。此外，我们发现一个涉及肌生成调节因子（MRFs）、Snai1/2、miR-30a和miR-206的调节网络作为控制进入肌生成分化的分子开关。总之，这些结果揭示了在祖细胞和终末分化细胞中指导不同基因表达程序的调控范式。
In skeletal myogenesis, the transcription factor MyoD activates distinct transcriptional programs in progenitors compared to terminally differentiated cells. Using ChIP-Seq and gene expression analyses, we show that in primary myoblasts, Snail-HDAC1/2 repressive complex binds and excludes MyoD from its targets. Notably, Snail binds E box motifs that are G/C rich in their central dinucleotides, and such sites are almost exclusively associated with genes expressed during differentiation. By contrast, Snail does not bind the A/T-rich E boxes associated with MyoD targets in myoblasts. Thus, Snai1-HDAC1/2 prevent MyoD occupancy on differentiation-specific regulatory elements, and the change from Snail to MyoD binding often results in enhancer switching during differentiation. Furthermore, we show that a regulatory network involving myogenic regulatory factors (MRFs), Snai1/2, miR-30a, and miR-206 acts as a molecular switch that controls entry into myogenic differentiation. Together, these results reveal a regulatory paradigm that directs distinct gene expression programs in progenitors versus terminally differentiated cells.