Abstract
Recent reports indicate that Smad7 promotes skeletal muscle differentiation and growth. We previously documented a non-canonical role of nuclear Smad7 during myogenesis, independent of its role in TGF-β signaling. Here further characterization of the myogenic function of Smad7 revealed β-catenin as a Smad7 interacting protein. Biochemical analysis identified a Smad7 interaction domain (SID) between aa575 and aa683 of β-catenin. Reporter gene analysis and chromatin immunoprecipitation demonstrated that Smad7 and β-catenin are cooperatively recruited to the extensively characterized ckm promoter proximal region to facilitate its muscle restricted transcriptional activation in myogenic cells. Depletion of endogenous Smad7 and β-catenin in muscle cells reduced ckm promoter activity indicating their role during myogenesis. Deletion of the β-catenin SID substantially reduced the effect of Smad7 on the ckm promoter and exogenous expression of SID abolished β-catenin function, indicating that SID functions as a trans dominant-negative regulator of β-catenin activity. β-catenin interaction with the Mediator kinase complex through its Med12 subunit led us to identify MED13 as an additional Smad7-binding partner. Collectively, these studies document a novel function of a Smad7-MED12/13-β-catenin complex at the ckm locus, indicating a key role of this complex in the program of myogenic gene expression underlying skeletal muscle development and regeneration.
Highlights
Developmental myogenesis, the process of terminal differentiation of skeletal muscle progenitor cells, consists of a series of well-characterized highly regulated steps that has become a paradigm for lineage acquisition and cellular differentiation[1,2,3,4,5]
The multisubunit compositional complexity of the Mediator holocomplex has proved a substantial challenge to define the full extent of its properties but what is apparent is that its fundamental role is to provide a functional bridge between transcriptional regulatory proteins bound to gene enhancers and the general transcription machinery assembled at core promoters[47,48,49,50,51,52,53]
The interaction of different Mediator subunits with a variety of transcription factors allows a myriad of cellular signaling events that converge on the transcription factors to be subsequently relayed to the transcriptional machinery and programs of gene transcription[54]
Summary
Developmental myogenesis, the process of terminal differentiation of skeletal muscle progenitor cells, consists of a series of well-characterized highly regulated steps that has become a paradigm for lineage acquisition and cellular differentiation[1,2,3,4,5]. Extensive biochemical and genetic evidence has implicated a family of DNA-binding transcriptional regulatory proteins encoded by the myogenic regulatory factor (MRF) genes, myf[5], myod[1], myogenin (myog), and mrf[4], in myogenesis[10,13]. In conjunction with the proteins encoded by the myocyte enhancer factor 2 (mef2a-d) gene family, the MRF’s activate an evolutionarily conserved program of gene expression, which leads to the generation of terminally differentiated skeletal muscle cells[14,15,16].
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