Basic helix-loop-helix factors recruit nuclear factor I to enhance expression of the NaV 1.4 Na+ channel gene

Sadie L. Hebert, Christine Simmons, Amy L. Thompson, Catherine S. Zorc, Eric M. Blalock, Susan D. Kraner

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

We have previously shown that the basic helix-loop-helix (bHLH) transcription factors coordinate NaV 1.4 Na+ channel gene expression in skeletal muscle, but the identity of the co-factors they direct is unknown. Using C2C12 muscle cells as a model system, we test the hypothesis that the bHLH factors counteract negative regulation exerted through a repressor E box (- 90/- 85) by recruiting positive-acting transcription factors to the nucleotides (- 135/- 57) surrounding the repressor E box. We used electrophoretic mobility shift assays to identify candidate factors that bound the repressor E box or these adjacent regions. Repressor E box-binding factors included the known transcription factor, ZEB/AREB6, and a novel repressor E box-binding factor designated REB. Mutations of the repressor E box that interfere with the binding of these factors prevented repression. The transcription factor, nuclear factor I (NFI), bound immediately upstream and downstream of the repressor E box. Mutation of the NFI-binding sites diminished the ability of myogenin and MRF4 to counteract repression. Based on these observations we suggest that bHLH factors recruit NFI to enhance skeletal muscle Na+ channel expression.

Original languageEnglish (US)
Pages (from-to)649-658
Number of pages10
JournalBiochimica et Biophysica Acta - Gene Structure and Expression
Volume1769
Issue number11-12
DOIs
StatePublished - Nov 2007

Keywords

  • GABP
  • MRF4
  • Myogenin
  • NFI
  • Neuromuscular junction
  • Skeletal muscle
  • Synaptogenesis

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