A non-canonical E-box within the MyoD core enhancer is necessary for circadian expression in skeletal muscle

Xiping Zhang, Samir P. Patel, John J. McCarthy, Alexander G. Rabchevsky, David J. Goldhamer, Karyn A. Esser

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The myogenic differentiation 1 (MyoD) gene is a master regulator of myogenesis. We previously reported that the expression of MyoD mRNA oscillates over 24h in skeletal muscle and that the circadian clock transcription factors, BMAL1 (brain and muscle ARNT-like 1) and CLOCK (circadian locomotor output cycles kaput), were bound to the core enhancer (CE) of the MyoD gene in vivo. In this study, we provide in vivo and in vitro evidence that the CE is necessary for circadian expression of MyoD in adult muscle. Gel shift assays identified a conserved non-canonical E-box within the CE that is bound by CLOCK and BMAL1. Functional analysis revealed that this E-box was required for full activation by BMAL1/CLOCK and for in vitro circadian oscillation. Expression profiling of muscle of CEloxP/loxP mice found approximately 1300 genes mis-expressed relative to wild-type. Based on the informatics results, we analyzed the respiratory function of mitochondria isolated from wild-type and CEloxP/loxP mice. These assays determined that State 5 respiration was significantly reduced in CEloxP/loxP muscle. The results of this work identify a novel element in the MyoD enhancer that confers circadian regulation to MyoD in skeletal muscle and suggest that loss of circadian regulation leads to changes in myogenic expression and downstream mitochondrial function.

Original languageEnglish
Pages (from-to)3419-3430
Number of pages12
JournalNucleic Acids Research
Volume40
Issue number8
DOIs
StatePublished - Apr 2012

Bibliographical note

Funding Information:
The National Institutes of Health (R01AR055246 to K.A.E., R01AR44878 to D.J.G.). Funding for open access charge: NIH (R01AR055246).

ASJC Scopus subject areas

  • Genetics

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