MYOD1 functions as a clock amplifier as well as a critical co-factor for downstream circadian gene expression in muscle

• Published in: eLife Vol. 8
• Main Authors: Hodge, Brian A, Zhang, Xiping, Gutierrez-Monreal, Miguel A, Cao, Yi, Hammers, David W, Yao, Zizhen, Wolff, Christopher A, Du, Ping, Kemler, Denise, Judge, Andrew R, Esser, Karyn A
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 21-02-2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; ARNTL Transcription Factors - metabolism; Binding sites; Bmal1; BMAL1 protein; Cell Biology; Chromosomes and Gene Expression; Circadian Clocks; Circadian rhythm; Circadian Rhythm Signaling Peptides and Proteins - biosynthesis; Circadian rhythms; clock; CLOCK Proteins - metabolism; Complementation; Connectin; Connectin - metabolism; Fluorescence; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genomics; Mice, Inbred C57BL; muscle transcription; Muscle, Skeletal - enzymology; Musculoskeletal system; MyoD Protein - metabolism; Ontology; Physiology; Plasmids; Skeletal muscle; Transcription factors; Canada; United States > US; mouse; cell biology; chromosomes; circadian rhythm; muscle transcription; clock; Bmal1; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.43017

In the present study we show that the master myogenic regulatory factor, MYOD1, is a positive modulator of molecular clock amplitude and functions with the core clock factors for expression of clock-controlled genes in skeletal muscle. We demonstrate that MYOD1 directly regulates the expression and circadian amplitude of the positive core clock factor
. We identify a non-canonical E-box element in
and demonstrate that is required for full MYOD1-responsiveness. Bimolecular fluorescence complementation assays demonstrate that MYOD1 colocalizes with both BMAL1 and CLOCK throughout myonuclei. We demonstrate that MYOD1 and BMAL1:CLOCK work in a synergistic fashion through a tandem E-box to regulate the expression and amplitude of the muscle specific clock-controlled gene, Titin-cap (
). In conclusion, these findings reveal mechanistic roles for the muscle specific transcription factor MYOD1 in the regulation of molecular clock amplitude as well as synergistic regulation of clock-controlled genes in skeletal muscle.