DNA methyltransferase 3a and mitogen-activated protein kinase signaling regulate the expression of fibroblast growth factor-inducible 14 (Fn14) during denervation-induced skeletal muscle atrophy.

Tajrishi MM, Shin J, Hetman M, Kumar A
J Biol Chem. 2014 289 (29): 19985-99

PMID: 24895120 · PMCID: PMC4106317 · DOI:10.1074/jbc.M114.568626

The TWEAK-fibroblast growth factor-inducible 14 (Fn14) system is a critical regulator of denervation-induced skeletal muscle atrophy. Although the expression of Fn14 is a rate-limiting step in muscle atrophy on denervation, mechanisms regulating gene expression of Fn14 remain unknown. Methylation of CpG sites within promoter region is an important epigenetic mechanism for gene silencing. Our study demonstrates that Fn14 promoter contains a CpG island close to transcription start site. Fn14 promoter also contains multiple consensus DNA sequence for transcription factors activator protein 1 (AP1) and specificity protein 1 (SP1). Denervation diminishes overall genomic DNA methylation and causes hypomethylation at specific CpG sites in Fn14 promoter leading to the increased gene expression of Fn14 in skeletal muscle. Abundance of DNA methyltransferase 3a (Dnmt3a) and its interaction with Fn14 promoter are repressed in denervated skeletal muscle of mice. Overexpression of Dnmt3a inhibits the gene expression of Fn14 and attenuates skeletal muscle atrophy upon denervation. Denervation also causes the activation of ERK1/2, JNK1/2, and ERK5 MAPKs and AP1 and SP1, which stimulate the expression of Fn14 in skeletal muscle. Collectively, our study provides novel evidence that Dnmt3a and MAPK signaling regulate the levels of Fn14 in skeletal muscle on denervation.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (24)

Animals Base Sequence Conserved Sequence CpG Islands DNA DNA (Cytosine-5-)-Methyltransferases DNA Methylation Gene Expression Gene Knockdown Techniques MAP Kinase Signaling System Mice Mice, Inbred C57BL Models, Biological Molecular Sequence Data Muscle, Skeletal Muscle Denervation Muscular Atrophy Promoter Regions, Genetic Receptors, Tumor Necrosis Factor RNA, Small Interfering Sequence Homology, Nucleic Acid Sp1 Transcription Factor Transcription Factor AP-1 TWEAK Receptor

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