Abstract
BackgroundSox6 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Sox6 is a multi-faceted transcription factor involved in the terminal differentiation of many different cell types in vertebrates
We proposed that Sox6 functions as a suppressor of slow fiber specific genes, the loss of Sox6 leads to an increase in slow muscle fibers
Fetal isoform gene expression is upregulated in the Sox6 KO heart Since the two cardiac myosin heavy chain (MyHC) isoform genes, a and b (Myh6 and Myh7), were associated with Sox6 binding (Additional file 3, Figure S2B) and their expression was upregulated in Sox6 KO skeletal muscle (Figure 5, Table 2), we examined their expression in the Sox6 KO heart
Summary
Sox is a multi-faceted transcription factor involved in the terminal differentiation of many different cell types in vertebrates. Skeletal muscle in vertebrates has evolved to be a major organ system with great adaptability in order to respond to constantly changing physical demands placed upon it This adaptability is achieved by the ability of muscle fibers to change their contractile and metabolic properties. We have previously reported that Sox mutant fetal and perinatal skeletal muscle exhibits a significant increase in slow fiber type-specific gene expression accompanied by a significant decrease in fast fiber typespecific gene expression [12,13]. Based on these observations, we have proposed that Sox functions as a transcriptional suppressor of slow fiber specific genes in developing skeletal muscle
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