Transcription Enhancer Factor 1 Binds Multiple Muscle MEF2 and A/T-Rich Elements during Fast-to-Slow Skeletal Muscle Fiber Type Transitions

Abstract

In adult mouse skeletal muscle, ␤-myosin heavy chain (␤MyHC) gene expression is primarily restricted to slow type I fibers; however, its expression can be induced in fast type II fibers in response to a sustained increase in load-bearing work (mechanical overload [MOV]). Our previous ␤MyHC transgenic and protein-DNA interaction studies have identified an A/T-rich element (␤A/T-rich ؊269/؊258) that is required for slow muscle expression and which potentiates MOV responsiveness of a 293-bp ␤MyHC promoter (␤293wt). Despite the GATA/MEF2-like homology of this element, we found binding of two unknown proteins that were antigenically distinct from GATA and MEF2 isoforms. By using the ␤A/T-rich element as bait in a yeast onehybrid screen of an MOV-plantaris cDNA library, we identified nominal transcription enhancer factor 1 (NTEF-1) as the specific ␤A/T-rich binding factor. Electrophoretic mobility shift assay analysis confirmed that NTEF-1 represents the enriched binding activity obtained only when the ␤A/T-rich element is reacted with MOV-plantaris nuclear extract. Moreover, we show that TEF proteins bind MEF2 elements located in the control region of a select set of muscle genes. In transient-coexpression assays using mouse C2C12 myotubes, TEF proteins transcriptionally activated a 293-bp ␤MyHC promoter devoid of any muscle CAT (MCAT) sites, as well as a minimal thymidine kinase promoter-luciferase reporter gene driven by three tandem copies of the desmin MEF2 or palindromic Mt elements or four tandem ␤A/T-rich elements. These novel findings suggest that in addition to exerting a regulatory effect by binding MCAT elements, TEF proteins likely contribute to regulation of skeletal, cardiac, and smooth muscle gene networks by binding select A/T-rich and MEF2 elements under basal and hypertrophic conditions.

An initial blueprint for myogenic differentiation

“…By binding M-CAT sites, TEAD4 participates in muscle-fiber-type switching and mediates in part the transcriptional effects of hypoxia and ␣-adrenergicstimulated muscular hypertrophy (Karasseva et al 2003;Shie et al 2004). Together with the observation that the M-CAT sequence is enriched among MRF targets, this suggests that, besides regulating additional genes during the muscle hypertrophic response (Ueyama et al 2000), TEAD4 propagates the myogenic signal originating from MyoD and cooperates with MRFs to induce the expression of their targets.…”

“…TEAD4 is closely related to TEAD1 (TEF-1), the founding member of a family of transcriptional regulators that bind M-CAT DNA elements (GGAATG) (Karasseva et al 2003). By binding M-CAT sites, TEAD4 participates in muscle-fiber-type switching and mediates in part the transcriptional effects of hypoxia and ␣-adrenergicstimulated muscular hypertrophy (Karasseva et al 2003;Shie et al 2004).…”

The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members

“…TEF-1 binds to MCAT sequences [related to CATTCC(A/T)] or A/T-rich sites within the promoter region of many genes, including βMHC (β-myosin heavy chain), cardiac troponin T and skeletal α-actin [1,2]. The above results show that TAZ and YAP65 interact with TEF-1, but the significance of this interaction to transcriptional regulation depends on these interactions occurring while TEF-1 is bound to DNA.…”

“…TEF-1 binds to MCAT (muscle C, A and T sites), sequence related to CATTCC(A/T), in promoters active in cardiac, skeletal and smooth muscle, placenta, and neural crest. Recently, R. Tsika and co-workers found that TEF-1 binds weakly to A/Trich binding sites in muscle promoters [2], expanding the promoters that are potentially regulated by TEF-1. The vast majority of cellular promoters that are MCAT-dependent are muscle-specific [1,[3][4][5].…”

Fgfr4 Is Required for Effective Muscle Regeneration in Vivo

“…Recent studies have also suggested that Tead1 binds to and activates A/T-rich and MEF2 elements on some muscle genes (50). The M-CAT motif was initially identified in the cardiac troponin T promoter, and the interaction of M-CAT motif and an M-CAT binding factor is required for the activation of cardiac troponin T promoter in muscle cells (51).…”