| Autor: |
Ehrlich KC; Program in Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA., Paterson HL; Neuroscience Program, Tulane University, New Orleans, LA., Lacey M; Tulane Cancer Center, Tulane University Health Sciences Center, New Orleans, LA; Mathematics Department, Tulane University, New Orleans, LA., Ehrlich M; 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. |
| Abstrakt: |
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., CASQ1 and FBXO32 , 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 myogenic MYOD1 gene in both SkM and myoblasts even though SkM has < 1 percent as much MYOD1 expression. 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 within MYOD1 '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. |
