Genome-wide mapping of Sox6 binding sites in skeletal muscle reveals both direct and indirect regulation of muscle terminal differentiation by Sox6.
Genome-wide mapping of Sox6 binding sites in skeletal muscle reveals both direct and indirect regulation of muscle terminal differentiation by Sox6.
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骨骼肌中Sox6结合位点的全基因组映射揭示了Sox6对肌肉末端分化的直接和间接调节。
DOI：
10.1186/1471-213x-11-59
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发表时间：
2011-10-10
影响因子：
--
通讯作者：
Hagiwara N
中科院分区：
文献类型：
--
作者：
An CI;Dong Y;Hagiwara N
Sox 6是一种多面转录因子，参与脊椎动物中许多不同细胞类型的终末分化。已经表明，在小鼠以及斑马鱼中，Sox 6通过抑制慢纤维特异性基因的转录在骨骼肌的终末分化中起作用。为了了解Sox 6如何在肌肉发育过程中协调调节多种纤维类型特异性基因的转录，我们进行了ChIP-seq分析以鉴定小鼠胎儿肌管中的Sox 6靶基因，并产生肌肉特异性Sox 6敲除（KO）小鼠以确定成年小鼠中的Sox 6缺失肌肉表型。我们已经确定了1,066 Sox 6结合位点使用小鼠胎儿肌管。发现Sox 6结合位点与肌节中表达的慢纤维特异性、心脏和胚胎同种型基因以及已知在肌肉发育中发挥作用的转录因子基因相关。同时进行的RNA聚合酶II（Pol II）ChIP-seq分析显示，84%的Sox 6峰相关基因几乎不结合Pol II，这表明大多数Sox 6靶基因在转录上是无活性的。这些结果表明Sox 6通过影响肌节蛋白基因的表达直接调节肌肉的终末分化，并通过影响与肌肉发育相关的转录因子的表达间接调节肌肉的终末分化。Sox 6 KO骨骼肌和心肌的基因表达谱显示与Sox 6结合相关的基因的表达显著增加。在Sox 6基因的情况下，有显着上调慢纤维特异性，心脏，胚胎亚型基因表达Sox 6 KO骨骼肌和胎儿亚型基因表达Sox 6 KO心肌，从而证实了Sox 6作为一个转录抑制在肌肉发育中发挥的作用。我们目前的数据表明，在发育过程中，Sox 6作为纤维类型特异性和发育同种型基因的转录抑制因子发挥作用，以促进肌肉的功能规范，这对最佳肌肉性能和健康至关重要。
Sox6 is a multi-faceted transcription factor involved in the terminal differentiation of many different cell types in vertebrates. It has been suggested that in mice as well as in zebrafish Sox6 plays a role in the terminal differentiation of skeletal muscle by suppressing transcription of slow fiber specific genes. In order to understand how Sox6 coordinately regulates the transcription of multiple fiber type specific genes during muscle development, we have performed ChIP-seq analyses to identify Sox6 target genes in mouse fetal myotubes and generated muscle-specific Sox6 knockout (KO) mice to determine the Sox6 null muscle phenotype in adult mice. We have identified 1,066 Sox6 binding sites using mouse fetal myotubes. The Sox6 binding sites were found to be associated with slow fiber-specific, cardiac, and embryonic isoform genes that are expressed in the sarcomere as well as transcription factor genes known to play roles in muscle development. The concurrently performed RNA polymerase II (Pol II) ChIP-seq analysis revealed that 84% of the Sox6 peak-associated genes exhibited little to no binding of Pol II, suggesting that the majority of the Sox6 target genes are transcriptionally inactive. These results indicate that Sox6 directly regulates terminal differentiation of muscle by affecting the expression of sarcomere protein genes as well as indirectly through influencing the expression of transcription factors relevant to muscle development. Gene expression profiling of Sox6 KO skeletal and cardiac muscle revealed a significant increase in the expression of the genes associated with Sox6 binding. In the absence of the Sox6 gene, there was dramatic upregulation of slow fiber-specific, cardiac, and embryonic isoform gene expression in Sox6 KO skeletal muscle and fetal isoform gene expression in Sox6 KO cardiac muscle, thus confirming the role Sox6 plays as a transcriptional suppressor in muscle development. Our present data indicate that during development, Sox6 functions as a transcriptional suppressor of fiber type-specific and developmental isoform genes to promote functional specification of muscle which is critical for optimum muscle performance and health.