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

We have previously shown that the basic helix-loop-helix (bHLH) transcription factors coordinate Na(V) 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 fac...

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Bibliographic Details
Published in:Biochimica et biophysica acta 2007-11, Vol.1769 (11-12), p.649-658
Main Authors: Hebert, Sadie L, Simmons, Christine, Thompson, Amy L, Zorc, Catherine S, Blalock, Eric M, Kraner, Susan D
Format: Article
Language:English
Subjects:
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - physiology
E-Box Elements
Gene Expression Regulation
Homeodomain Proteins - physiology
Humans
Muscle Proteins - genetics
Muscle, Skeletal - metabolism
NAV1.4 Voltage-Gated Sodium Channel
NFI Transcription Factors - physiology
Phosphorylation
Sodium Channels - genetics
Transcription Factors - physiology
Zinc Finger E-box-Binding Homeobox 1
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Summary:We have previously shown that the basic helix-loop-helix (bHLH) transcription factors coordinate Na(V) 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.
ISSN:0006-3002
0167-4781
DOI:10.1016/j.bbaexp.2007.08.004