title: 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.
abstract: 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.
authors.affiliation: From the Departments of Anatomical Sciences and Neurobiology and.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Tajrishi
authors.affiliation: From the Departments of Anatomical Sciences and Neurobiology and.
authors.forename: Jonghyun
authors.initials: J
authors.lastname: Shin
authors.affiliation: Neurological Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40202.
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
authors.affiliation: From the Departments of Anatomical Sciences and Neurobiology and ashok.kumar@louisville.edu.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D018899:CpG Islands; D004247:DNA / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000378:metabolism; D000074050:TWEAK Receptor; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C000715535:Dnmt3a protein, mouse; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D016329:Sp1 Transcription Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D018808:Transcription Factor AP-1; D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: Cytokine; DNA Methyltransferase; Denervation; Epigenetics; Mitogen-activated Protein Kinase (MAPK); Muscle Atrophy; Skeletal Muscle; Specificity Protein 1 (Sp1); TWEAK-Fn14 System; Transcription Factor