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Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6.

ABSTRACT: In response to physiological stimuli, skeletal muscle alters its myofiber composition to significantly affect muscle performance and metabolism. This process requires concerted regulation of myofiber-specific isoforms of sarcomeric and calcium regulatory proteins that couple action potentials to the generation of contractile force. Here, we identify Sox6 as a fast myofiber-enriched repressor of slow muscle gene expression in vivo. Mice lacking Sox6 specifically in skeletal muscle have an increased number of slow myofibers, elevated mitochondrial activity, and exhibit down-regulation of the fast myofiber gene program, resulting in enhanced muscular endurance. In addition, microarray profiling of Sox6 knockout muscle revealed extensive muscle fiber-type remodeling, and identified numerous genes that display distinctive fiber-type enrichment. Sox6 directly represses the transcription of slow myofiber-enriched genes by binding to conserved cis-regulatory elements. These results identify Sox6 as a robust regulator of muscle contractile phenotype and metabolism, and elucidate a mechanism by which functionally related muscle fiber-type specific gene isoforms are collectively controlled.

SUBMITTER: Quiat D

PROVIDER: S-EPMC3121857 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6.

Quiat Daniel D Voelker Kevin A KA Pei Jimin J Grishin Nick V NV Grange Robert W RW Bassel-Duby Rhonda R Olson Eric N EN

Proceedings of the National Academy of Sciences of the United States of America 20110601 25

In response to physiological stimuli, skeletal muscle alters its myofiber composition to significantly affect muscle performance and metabolism. This process requires concerted regulation of myofiber-specific isoforms of sarcomeric and calcium regulatory proteins that couple action potentials to the generation of contractile force. Here, we identify Sox6 as a fast myofiber-enriched repressor of slow muscle gene expression in vivo. Mice lacking Sox6 specifically in skeletal muscle have an increas ...[more]

PMID: 21633012

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Project description:BackgroundTissue regeneration requires a series of steps, beginning with generation of the necessary cell mass, followed by cell migration into damaged area, and ending with differentiation and integration with surrounding tissues. Temporal regulation of these steps lies at the heart of the regenerative process, yet its basis is not well understood. The ability of zebrafish to dedifferentiate mature "post-mitotic" myocytes into proliferating myoblasts that in turn regenerate lost muscle tissue provides an opportunity to probe the molecular mechanisms of regeneration.ResultsFollowing subtotal excision of adult zebrafish lateral rectus muscle, dedifferentiating residual myocytes were collected at two time points prior to cell cycle reentry and compared to uninjured muscles using RNA-seq. Functional annotation (GAGE or K-means clustering followed by GO enrichment) revealed a coordinated response encompassing epigenetic regulation of transcription, RNA processing, and DNA replication and repair, along with protein degradation and translation that would rewire the cellular proteome and metabolome. Selected candidate genes were phenotypically validated in vivo by morpholino knockdown. Rapidly induced gene products, such as the Polycomb group factors Ezh2 and Suz12a, were necessary for both efficient dedifferentiation (i.e. cell reprogramming leading to cell cycle reentry) and complete anatomic regeneration. In contrast, the late activated gene fibronectin was important for efficient anatomic muscle regeneration but not for the early step of myocyte cell cycle reentry.ConclusionsReprogramming of a "post-mitotic" myocyte into a dedifferentiated myoblast requires a complex coordinated effort that reshapes the cellular proteome and rewires metabolic pathways mediated by heritable yet nuanced epigenetic alterations and molecular switches, including transcription factors and non-coding RNAs. Our studies show that temporal regulation of gene expression is programmatically linked to distinct steps in the regeneration process, with immediate early expression driving dedifferentiation and reprogramming, and later expression facilitating anatomical regeneration.

Project description: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.

Project description:Parkinson's disease (PD) is a common neurodegenerative disorder impacting cognition, movement, and quality of life in >10 million individuals worldwide. We recently characterized and quantified a skeletal muscle pathology in PD represented by exaggerated type I myofiber grouping presumed to result from denervation-reinnervation processes. Our previous findings indicated that impaired neuromuscular junction integrity may be involved in type I grouping, which is associated with excessive motor unit activation during weight-bearing tasks. In this study, we performed transcriptional profiling to test the hypothesis that type I grouping severity would link to distinct gene expression networks. We generated transcriptome-wide poly(A) RNA-Seq data from skeletal muscle of individuals with PD [n = 12 (9 men, 3 women); 67 ± 2 yr], age- and sex-matched older adults (n = 12; 68 ± 2 yr), and sex-matched young adults (n = 12; 30 ± 1 yr). Differentially expressed genes were evaluated across cohorts. Weighted gene correlation network analysis (WGCNA) was performed to identify gene networks most correlated with indicators of abnormal type I grouping. Among coexpression networks mapping to phenotypes pathologically increased in PD muscle, one network was highly significantly correlated to type I myofiber group size and another to percentage of type I myofibers found in groups. Annotation of coexpressed networks revealed that type I grouping is associated with altered expression of genes involved in neural development, postsynaptic signaling, cell cycle regulation and cell survival, protein and energy metabolism, inflammation/immunity, and posttranscriptional regulation (microRNAs). These transcriptomic findings suggest that skeletal muscle may play an active role in signaling to promote myofiber survival, reinnervation, and remodeling, perhaps to an extreme in PD.NEW & NOTEWORTHY Despite our awareness of the impact of Parkinson's disease (PD) on motor function for over two centuries, limited attention has focused on skeletal muscle. We previously identified type I myofiber grouping, a novel indicator of muscle dysfunction in PD, presumably a result of heightened rates of denervation/reinnervation. Using transcriptional profiling to identify networks associated with this phenotype, we provide insight into potential mechanistic roles of skeletal muscle in signaling to promote its survival in PD.

Dataset Information

Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6.

Publications

Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6.

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