title: DNA Hypomethylation in Intragenic and Intergenic Enhancer Chromatin of Muscle-Specific Genes Usually Correlates with their Expression.
abstract: Tissue-specific enhancers are critical for gene regulation. In this study, we help elucidate the contribution of muscle-associated differential DNA methylation to the enhancer activity of highly muscle-specific genes. By bioinformatic analysis of 44 muscle-associated genes, we show that preferential gene expression in skeletal muscle (SkM) correlates with SkM-specific intragenic and intergenic enhancer chromatin and overlapping foci of DNA hypomethylation. Some genes, e.g.,CASQ1andFBXO32, displayed broad regions of both SkM- and heart-specific enhancer chromatin but exhibited focal SkM-specific DNA hypomethylation. Half of the genes had SkM-specific super-enhancers. In contrast to simple enhancer/gene-expression correlations, a super-enhancer was associated with the myogenicMYOD1gene in both SkM and myoblasts even though SkM has < 1 percent as muchMYOD1expression. Local chromatin differences in this super-enhancer probably contribute to the SkM/myoblast differential expression. Transfection assays confirmed the tissue-specificity of the 0.3-kb core enhancer withinMYOD1's super-enhancer and demonstrated its repression by methylation of its three CG dinucleotides. Our study suggests that DNA hypomethylation increases enhancer tissue-specificity and that SkM super-enhancers sometimes are poised for physiologically important, rapid up-regulation.
authors.affiliation: Program in Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Ehrlich
authors.affiliation: Neuroscience Program, Tulane University, New Orleans, LA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Paterson
authors.affiliation: Tulane Cancer Center, Tulane University Health Sciences Center, New Orleans, LA; Mathematics Department, Tulane University, New Orleans, LA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lacey
authors.affiliation: Program in Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA; Tulane Cancer Center, Tulane University Health Sciences Center, New Orleans, LA; Hayward Genetics Center, Tulane University Health Sciences Center, New Orleans, LA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ehrlich
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics; D002155:Calsequestrin; D045744:Cell Line, Tumor; D019295:Computational Biology; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D024101:Mitochondrial Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics
chemical_list: C503129:CASQ1 protein, human; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases
keywords: CASQ1; DNA methylation; FBXO32; HOXC gene cluster; MYOD; PRKAG3; development; enhancers; heart; promoters; skeletal muscle