Article

Genome-wide mapping of Sox6 binding sites in skeletal muscle reveals both direct and indirect regulation of muscle terminal differentiation by Sox6

Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, One Shields Avenue, Davis, California 95616, USA.
BMC Developmental Biology (Impact Factor: 2.75). 10/2011; 11:59. DOI: 10.1186/1471-213X-11-59
Source: PubMed

ABSTRACT 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.

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    • "The slow-fiber type program appears to be partially promoted by PGC-1 (Rasbach, Gupta et al. 2010, Summermatter, Thurnheer et al. 2012), PPARγ (Luquet, Lopez-Soriano et al. 2003) and MEF2 (Wu, Naya et al. 2000). At the transcriptional level the slow program can be enhanced by Pdrm1a which represses the transcriptional factor Sox 6 (von Hofsten, Elworthy et al. 2008, Wang, Ono et al. 2011), a transcriptional repressor of the slow-fiber type program (Hagiwara, Ma et al. 2005, Quiat, Voelker et al. 2011). The fast-fiber type program is dependent upon the six transcriptional complex (STC), where elimination of Six1, Six4 and the cofactor Eya1 can prevent fast-twitch muscle fiber formation (Grifone, Laclef et al. 2004, Niro, Demignon et al. 2010, Richard, Demignon et al. 2011). "
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    • "The final collection of datasets contained 191 GEO series containing a total of 917 ChIP-seq and 292 control libraries. Except for a limited number of cases in which a GEO series was associated with multiple publications, two or three GEO series were associated with the same publication, or a GEO series has not yet been used in a publication, and there is a one-to-one relationship between GEO series and published articles in the literature (Robertson et al. 2007; Chen et al. 2008; Marson et al. 2008; Bilodeau et al. 2009; Cheng et al. 2009; De Santa et al. 2009; Lister et al. 2009; Nishiyama et al. 2009; Visel et al. 2009; Welboren et al. 2009; Wilson et al. 2009; Yu et al. 2009; Yuan et al. 2009; Barish et al. 2010; Blow et al. 2010; Blow et al. 2010; Cao et al. 2010; Chi et al. 2010; Chia et al. 2010; Chicas et al. 2010; Corbo et al. 2010; Cuddapah et al. 2009; Durant et al. 2010; Fortschegger et al. 2010; Gotea et al. 2010; Gu et al. 2010; Han et al. 2010; Heinz et al. 2010; Heng et al. 2010; Ho et al. 2009; Hollenhorst et al. 2009; Hu et al. 2010; Johannes et al. 2010; Jung et al. 2010; Kagey et al. 2010; Kassouf et al. 2010; Kim et al. 2010; Kong et al. 2010; Kouwenhoven et al. 2010; Krebs et al. 2010; Kunarso et al. 2010; Kwon et al. 2009; Law et al. 2010; Lee et al. 2010; Lefterova et al. 2010; Li et al. 2010; Lin et al. 2010; Liu et al. 2010; Ma et al. 2010; MacIsaac et al. 2010; Mahony et al. 2010; Martinez et al. 2010; Palii et al. 2010; Qi et al. 2010; Rada-Iglesias et al. 2010; Rahl et al. 2010; Ramagopalan et al. 2010; Ramos et al. 2010; Schlesinger et al. 2010; Schnetz et al. 2010; Sehat et al. 2010; Steger et al. 2010; Tallack et al. 2010; Tang et al. 2010; Vermeulen et al. 2010; Verzi et al. 2010; Vivar et al. 2010; Wei et al. 2010; Woodfield et al. 2010; Yang et al. 2010; Yao et al. 2010; Yu et al. 2010; An et al. 2011; Ang et al. 2011; Bergsland et al. 2011; Bernt et al. 2011; Botcheva et al. 2011; Brown et al. 2011; Bugge et al. 2011; Ceol et al. 2011; Ceschin et al. 2011; Costessi et al. 2011; Ebert et al. 2011; Fang et al. 2011; Handoko et al. 2011; He et al. 2011; Heikkinen et al. 2011; Holmstrom et al. 2011; Horiuchi et al. 2011; Hu et al. 2011; Joseph et al. 2010; Kim et al. 2011; Klisch et al. 2011; Koeppel et al. 2011; Kong et al. 2011; Little et al. 2011; Liu et al. 2011; Lo et al. 2011; Marban et al. 2011; Mazzoni et al. 2011; McManus et al. 2011; Mendoza-Parra et al. 2011; Meyer et al. 2012; Miyazaki et al. 2011; Mullen et al. 2011; Mullican et al. 2011; Nakayamada et al. 2011; Nitzsche et al. 2011; Norton et al. 2011; Novershtern et al. 2011; Quenneville et al. 2011; Rao et al. 2011; Rey et al. 2011; Sahu et al. 2011; Schmitz et al. 2011; Seitz et al. 2011; Shen et al. 2011; Shukla et al. 2011; Siersbæk et al. 2011; Smeenk et al. 2011; Smith et al. 2011; Soccio et al. 2011; Stadler et al. 2011; Sun et al. 2011; Tan et al. 2011a; Tan et al. 2011b; Teo et al. 2011; Tijssen et al. 2011; Tiwari et al. 2011a; Tiwari et al. 2011b; Trompouki et al. 2011; van Heeringen et al. 2011; Verzi et al. 2011; Wang et al. 2011a; Wang et al. 2011b; Wei et al. 2011; Whyte et al. 2011; Wu et al. 2011a; Wu et al. 2011b; Xu et al. 2011; Yang et al. 2011; Yildirim et al. 2011; Yoon et al. 2011; Zhang et al. 2011; Zhao et al. 2011a; Zhao et al. 2011b; Avvakumov et al. 2012; Barish et al. 2012; Boergesen et al. 2012; Bugge et al. 2012; Canella et al. 2012; Cardamone et al. 2012; Cheng et al. 2012; Chlon et al. 2012; Cho et al. 2012; Doré et al. 2012; Fan et al. 2012; Feng et al. 2011; Fong et al. 2012; Gao et al. 2012; Gowher et al. 2012; Hunkapiller et al. 2012; Hutchins et al. 2012; Li et al. 2012; Lu et al. 2012; Miller et al. 2011; Ntziachristos et al. 2012; Pehkonen et al. 2012; Ptasinska et al. 2012; Remeseiro et al. 2012; Sadasivam et al. 2012; Sakabe et al. 2012; Schödel et al. 2012; Trowbridge et al. 2012; Vilagos et al. 2012; Wu et al. 2012; Xiao et al. 2012; Yu et al. 2012; unpublished at the time of completion of this manuscript are the following GEO accession numbers: GSE33346, GSE33850, GSE36561, GSE30919, GSE33128, GSE35109, GSE25426, GSE31951, GSE26711, GSE23581, GSE26136, GSE26680, GSE15844, GSE21916, GSE22303, and GSE29180; direct links to all GEO series can be found in Table S1). "
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