Stephen J Palmer | PubMed Health

PubMed2006

MusTRD can regulate postnatal fiber-specific expression.

Human MusTRD1alpha1 was isolated as a result of its ability to bind a critical element within the Troponin I slow upstream enhancer (TnIslow USE) and was predicted to be a regulator of slow fiber-specific genes. To test this hypothesis in vivo, we generated transgenic mice expressing hMusTRD1alpha1 in skeletal muscle. Adult transgenic mice show a complete loss of slow fibers and a concomitant replacement by fast IIA fibers, resulting in postural muscle weakness. However, developmental analysis demonstrates that transgene expression has no impact on embryonic patterning of slow fibers but causes a gradual postnatal slow to fast fiber conversion. This conversion was underpinned by a demonstrable repression of many slow fiber-specific genes, whereas fast fiber-specific gene expression was either unchanged or enhanced. These data are consistent with our initial predictions for hMusTRD1alpha1 and suggest that slow fiber genes contain a specific common regulatory element that can be targeted by MusTRD proteins.

Animals↗

PubMed2003

hMusTRD1alpha1 represses MEF2 activation of the troponin I slow enhancer.

The novel transcription factor hMusTRD1alpha1 (human muscle TFII-I repeat domain-containing protein 1alpha1; previously named MusTRD1; O'Mahoney, J. V., Guven, K. L., Lin, J., Joya, J. E., Robinson, C. S., Wade, R. P., and Hardeman, E. C. (1998) Mol. Cell. Biol. 18, 6641-6652) was identified in a yeast one-hybrid screen as a protein that binds within an upstream enhancer-containing region of the skeletal muscle-specific gene, TNNI1 (human troponin I slow; hTnIslow). It has been proposed that hMusTRD1alpha1 may play an important role in fiber-specific muscle gene expression by virtue of its ability to bind to an Inr-like element (nucleotides -977 to -960) within the hTnIslow upstream enhancer-containing region that is necessary for slow fiber-specific expression. In this study we demonstrate that both MEF2C, a known regulator of slow fiber-specific genes, and hMusTRD1alpha1 regulate hTnIslow through the Inr-like element. Co-transfection assays in C2C12 cells and Cos-7 cells demonstrate that hMusTRD1alpha1 represses hTnIslow transcription and prevents MEF2C-mediated activation of hTnIslow transcription. Gel shift analysis shows that hMusTRD1alpha1 can abrogate MEF2C binding to its cognate site in the hTnIslow enhancer. Glutathione S-transferase pull-down assays demonstrate that hMusTRD1alpha1 can interact with both MEF2C and the nuclear receptor co-repressor. The data support the role of hMusTRD1alpha1 as a repressor of slow fiber-specific transcription through mechanisms involving direct interactions with MEF2C and the nuclear receptor co-repressor.

Animals↗