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Title: TBP/TFIID-dependent activation of MyoD target genes in skeletal muscle cells}
Article:
Abstract:
Change in the identity of the components of the transcription pre-initiation complex is proposed to control cell type-specific gene expression. Replacement of the canonical TFIID-TBP complex with TRF3/TBP2 was reported to be required for activation of muscle-gene expression. The lack of a developmental phenotype in TBP2 null mice prompted further analysis to determine whether TBP2 deficiency can compromise adult myogenesis. We show here that TBP2 null mice have an intact regeneration potential upon injury and that TBP2 is not expressed in established C2C12 muscle cell or in primary mouse MuSCs. While TFIID subunits and TBP are downregulated during myoblast differentiation, reduced amounts of these proteins form a complex that is detectable on promoters of muscle genes and is essential for their expression. This evidence demonstrates that TBP2 does not replace TBP during muscle differentiation, as previously proposed, with limiting amounts of TFIID-TBP being required to promote muscle-specific gene expression.
Introduction:
The process of RNA polymerase II( RNAPII) recruitment to protein coding genes is part of the assembly of the Pre-Initiation Complex( PIC) that is typically nucleated by TFIID-mediated recognition of core promoter sequences. The TFIID complex is composed of TATA-box binding protein( TBP) and TBP-associated factors( TAFs)( Roeder, 1996; Tora, 2002). Moreover, several TBP-related factors( TRFs) have been identified( Akhtar and Veenstra, 2011), expanding the repertoire and versatility of the basal transcription machinery( Müller et al., 2010; Goodrich and Tjian, 2010; Müller et al., 2007). While a number of events contribute to promote PIC assembly, including sequence-specific transcriptional activators, chromatin remodeling complexes and histone modifications, recent work has proposed that changes in the identity of PIC components is a key determinant of cell type-specific gene expression( Hart et al., 2007; Deato and Tjian, 2007). In particular, it was recently suggested that during skeletal muscle differentiation, canonical TFIID is replaced by a complex consisting of TBP2( also termed TRF3 = TBP-related factor 3; gene name Tbpl2 = TATA box binding protein like 2) and TAF3, which is required for activation of muscle genes( Deato and Tjian, 2007; Deato et al., 2008). Further work has revealed that the alternative core factor TAF3, which is known to recognize histone H3K4me3- a histone modification associated with active promoters( Vermeulen et al., 2007; van Ingen et al., 2008; Lauberth et al., 2013; Stijf-Bultsma et al., 2015)- mediates interactions between MyoD, permissive chromatin and PICs at promoters of muscle-specific genes( Deato et al., 2008; Yao et al., 2011). This finding suggested that the widely established paradigm of a universal and prevalent use of TFIID as a promoter-recognizing complex in a variety of somatic cells might undergo drastic change during development. Nevertheless this hypothesis has been challenged by the observation that TBP2 null( TBP2_KO = TBP2 knock out) mice do not display any skeletal muscle phenotype( Gazdag et al., 2009), indicating that TBP2 is dispensable for developmental myogenesis( see http://www. europhenome. org/databrowser/viewer. jsp? set=true&m=true&x=Both Split&ln=Tbp2&project=All&zygosity=All&m=true&l=10386). However, Gazdag et al. did not explore the integrity of the regeneration potential of skeletal muscles in TBP2 null mice during adult life, and thus have not ruled out the possibility that TBP2 can specifically promote the expression of muscle genes in muscle stem( satellite) cells( MuSCs)- the direct effectors of post-natal and adult skeletal myogenesis( Chang and Rudnicki, 2014). MuSCs are usually found beneath the basal lamina of unperturbed muscles in a dormant state( quiescence)( Mauro, 1961), but are rapidly activated upon damage to give rise to new, differentiated myofibers through extensive epigenetic reprogramming( Dilworth and Blais, 2011; Sartorelli and Juan, 2011; Moresi et al., 2015). Two key molecular events that invariably coincide with MuSC activation and commitment toward myogenic differentiation are( i) the expression of skeletal muscle transcription master regulator MyoD( Zammit et al., 2004; Tapscott, 1988) and( ii) the activation of the p38 signaling( Jones et al., 2005). These pathways cooperate to promote SWI/SNF-mediated chromatin remodeling and to increase levels of the active chromatin mark H3K4me3( Bernstein et al., 2005) at promoters of muscle genes( Simone, 2004; Rampalli et al., 2007; Forcales et al., 2012). Indeed, studies from the Rando group have revealed that in activated MuSCs the large majority of muscle gene promoters show enrichment in H3K4me3( Liu et al., 2013). Collectively, the data described above suggest that the H3K4me3 chromatin mark can mediate TAF3 recruitment to MyoD-target genes in activated MuSCs. Since TAF3 has been proposed as a mediator of TBP2 recruitment to muscle gene promoters( Deato et al., 2008; Yao et al., 2011), these data provide the rationale for investigating whether TBP2 deficiency can impair post-natal and adult skeletal myogenesis.
Discussion:
In this work, we demonstrate that TBP, but not TBP2, is the essential component of the PIC that promotes muscle gene expression in differentiated skeletal muscles. We found that TBP2 is not expressed in myotubes derived from either C2C12 myoblasts, nor from primary mouse MuSCs. Consistently, TBP2-deficient mice displayed an intact regeneration potential, and MuSCs isolated from TBP2-deficient muscles differentiated into myotubes with the same efficiency as wild type MuSCs. This evidence firmly supports the conclusion that TBP2 does not replace TBP during muscle differentiation, as previously proposed by Deato et al.( Deato and Tjian, 2007). We have observed downregulation of TFIID subunits at both the RNA and protein levels in differentiated myotubes, compared to proliferating myoblasts, as has previously been reported( Deato and Tjian, 2007; Zhou et al., 2013). Recently, a mechanism for ubiquitination-mediated downregulation of TBP protein in skeletal myotubes was reported( Li et al., 2015). Therefore, the plausible scenario in skeletal muscle specific transcription is that limited TFIID helps to restrict the assembly of the transcription competent PIC at a selected subset of muscle specific genes. Our findings that TBP/TFIID is functional in muscle progenitors and their differentiated progeny are in agreement with earlier studies showing that TBP was able to bind the MyoD promoter in a TATA-dependent manner( Leibham et al., 1994). It has been also shown that MyoD efficiently stimulated TFIID-dependent basal transcription( Heller and Bengal, 1998; Dilworth, 2004). Moreover, an endogenous interaction between MyoD and TBP in both myoblasts and myotubes was demonstrated, and in myotubes, MyoD and components of PIC TBP and TFIIB were found to be recruited to the proximal promoter of the alpha-sarcoglycan muscle gene promoter( Delgado-Olguín et al., 2006). The relevance of TBP-mediated activation of MyoD target genes has been recently emphasized by the finding that large polyglutamine( PolyQ) repeats in TBP causes muscle degeneration, by reducing the expression of muscle-specific genes, due to a decreased association of TBP with MyoD( Huang et al., 2015). This finding reiterates the importance of clarifying the identity of the proteins that compose the core promoter basal machinery required for muscle gene transcription in differentiating muscles, further extending the related implications to the pathogenesis of human muscular disorders. 10. 7554/eLife. 12534. 010Table 1. Squences of the primers used in this study. DOI: http://dx. doi. org/10. 7554/eLife. 12534. 010Mouse primers for RT-PCRGapdh-forGCTCACTGGCATGGCCTTCCGGapdh-revGTAGGCCATGAGGTCCACCACMyog-forGAGACATCCCCCTATTTCTACCAMyog-revGCTCAGTCCGCTCATAGCCActa1-forAOCGTTTCCGTTGCCCOOAGActa1-revGGAGAGAGAGCGCGAACGCATtn-forGACACCACAAGGTGCAAAGTCTtn-revCCCACTOTTCTTGACCGTATCTPdlim3-forTGGGGGCATAGACTTCAATCAPdlim3-revCTCCGTACCAAAGCCATCAATAGMylpf-forTTCAAGGAGGCGTTCACTQTAMylpf-revTAOCGTCOAGTTCCTCATTCTMybph-forCAGCCACTAAGCCTGAACCTCMybph-revTCCAACACATAGCCTTGAAGCCyclin D1-forACTTCCTCTCCAAAATGCCAGCyclin D1-revGTOGGTTGOAAATGAACTTCACCkm-forAQTCCTACACQQTCTTCAAGOCkm-revAGGAAGTGGTCATCAATQAGCTbpl2-forATACCTGGACCTCTTCCTGOATTbpl2-revCCACCAAGATGTGGATGAAACTbp-forCCAAGCGATTTGCTGCAGTCATCATbp-revACTTAGCTGGGAAGGCCAACTTCTTaf1-forACAGGAACAGATGCAGACCTTCGTTaf1-revAATCTCCTCCTCAGGCACACCAAATaf2-forGGCCTTGGAAAAATTCCCCACTaf2-revGAAGCACGCTGACATCCTGATaf3-forGACATTGATGCTGCGAAAGTGCGATaf3-revTCCCGCTTGCT7CTTTCTCGATCTTaf4-forAGTTCACACGGCAAAGAATCACGCTaf4-revAACGCCGGCTCATCCTGTTACTTATaf5-forTTTC6GACGAGTAAATTCGTTCTTaf5-revCTCCTGCACGATGTTCCAGATTaf6-forAAACTCAGCAATACTGTGTTGCCTaf6-revTTCTGTCGTTTCCCCATGTGCTaf8-forCCGGGAAGTAAGCAATCCACTTaf8-revGCTTTCTCGGCACTCTCAAATCTar9-forTGCCGAAAGATGCACAGATGATaf9-revTGTTGTCACATATCOGAAGGCTaf10-forGAGGGOGCAATQTCTAACGGTaf10-revTGTGTAATCCTCCAACTGCATCTaf12-forGGACAGQTQQTCGTCTCAGTat12-revTCATCAOCOATCTOTAGCAGCMouse primers for ChIPMyoq TSS-forGCTCAGGTTTCTGTGGCGTTMyog TSS-revCCAAC TGCTGGGTGCC ATActa1 T5S-forGTGCCCGACACCCAAATAActa1 TSS-revAGGGTAGGAAGTGAGGCTTTtn TSS-forCCTTCCTAACAGAGCCAATCACTtn TSS-revTGTTTCCTATGCAATCCCTACACPdlim3 TSS-forCACTCGCAGCAGGQATAAATPdlim3 TSS-revGAACCGGACAACCTACTTAGCMylpf TSS-forCTCCAAGCAGATTCTCTTGCTTTMylpf TSS-revGGTAGOGC TAT CC T OAOCTAATMybph TSS-forGCCTGCCTTTATAAGCATQAACMybph TSS-revGTOTCAAGCTGOAGTOTTTAAGGapdh TSS-forAGQGCTGCAGTCCGTATTTAGapdh TSS-revAGOAGGGGAAATGAGAOAGGSox2 TSS-forGATTGGCCGCCGQAAACSox2 TSS-revCTCTTCTCTOCCTTOACAACTCIgh enhancer-forAACCACAGCTACAAGTTTACCIgh enhancer-revAACCAGAAÇACCTGCAGCAGC
The muscles that allow animal’s to move are built predominantly of cells called myofibers . Like other specialized cell types , these myofibers develop via a regulated set of events called differentiation . In adults , this phenomenon occurs when muscles regenerate after an injury , and new myofibers differentiate from so-called satellite cells that already reside within the muscles . Differentiation is regulated at the genetic level , and the development of myofibers relies on the activation of muscle-specific genes . A gene’s expression is typically controlled via a nearby regulatory region of DNA called a promoter that can be recognized by various molecular machines made from protein complexes . In most adult tissues , such regulatory machineries contain a complex called TFIID . Previously it was reported that the TFIID complex was eliminated from cells during muscle differentiation , and that an alternative protein complex called TBP2/TAF3 recognizes and regulates the promoters of muscle-specific genes . However , Malecova et al . have now discovered that TFIID is actually present , albeit at reduced amounts , in differentiated muscles and that it drives the activation of muscle-specific genes during differentiation . Further experiments also showed that the TBP2 protein is not required for differentiation of muscle cells or for the regeneration of injured muscles , and is actually absent in muscle cells . Further studies are now needed to explore how the TFIID-containing complex works with other regulatory protein complexes that are known to help make muscle-specific genes accessible to TFIID . It will also be important to study the relationship between the down-regulation of TFIID components and the activation of muscle-specific genes that typically occurs in mature myofbers . Together these efforts will allow the various aspects of gene regulation to be integrated , which will help provide a more complete understanding of the process of muscle differentiation .