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Molecular and Cellular Biology, December 2001, p. 8490-8503, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8490-8503.2001

Molecular Dissection of DNA Sequences and Factors Involved in Slow Muscle-Specific Transcription

Soledad Calvo,dagger Detlef Vullhorst, Pratap Venepally,Dagger Jun Cheng, Irina Karavanova, and Andres Buonanno*

Section on Molecular Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Received 1 May 2001/Returned for modification 25 June 2001/Accepted 18 September 2001

Transcription is a major regulatory mechanism for the generation of slow- and fast-twitch myofibers. We previously identified an upstream region of the slow TnI gene (slow upstream regulatory element [SURE]) and an intronic region of the fast TnI gene (fast intronic regulatory element [FIRE]) that are sufficient to direct fiber type-specific transcription in transgenic mice. Here we demonstrate that the downstream half of TnI SURE, containing E box, NFAT, MEF-2, and CACC motifs, is sufficient to confer pan-skeletal muscle-specific expression in transgenic mice. However, upstream regions of SURE and FIRE are required for slow and fast fiber type specificity, respectively. By adding back upstream SURE sequences to the pan-muscle-specific enhancer, we delineated a 15-bp region necessary for slow muscle specificity. Using this sequence in a yeast one-hybrid screen, we isolated cDNAs for general transcription factor 3 (GTF3)/muscle TFII-I repeat domain-containing protein 1 (MusTRD1). GTF3 is a multidomain nuclear protein related to initiator element-binding transcription factor TF II-I; the genes for both proteins are deleted in persons with Williams-Beuren syndrome, who often manifest muscle weakness. Gel retardation assays revealed that full-length GTF3, as well as its carboxy-terminal half, specifically bind the bicoid-like motif of SURE (GTTAATCCG). GTF3 expression is neither muscle nor fiber type specific. Its levels are highest during a period of fetal development that coincides with the emergence of specific fiber types and transiently increases in regenerating muscles damaged by bupivacaine. We further show that transcription from TnI SURE is repressed by GTF3 when overexpressed in electroporated adult soleus muscles. These results suggest a role for GTF3 as a regulator of slow TnI expression during early stages of muscle development and suggest how it could contribute to Williams-Beuren syndrome.

* Corresponding author. Mailing address: Section on Molecular Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-3298. Fax: (301) 496-9939. E-mail: buonanno{at}helix.nih.gov.

dagger Present address: Universidad de Castilla la Mancha, Facultad de Medicina, Albacete 02071, Spain.

Dagger Present address: National Center for Biotechnology Information, NIH, Bethesda, MD 20894.

Molecular and Cellular Biology, December 2001, p. 8490-8503, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8490-8503.2001


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