| Summary: | <b> </b>Much remains to be discovered about the intersection of tissue-specific transcription control and the epigenetics of skeletal muscle (SkM), a very complex and dynamic organ. From four gene families, Leucine-Rich Repeat Containing<i> (LRRC)</i>, Oxysterol Binding Protein Like<i> (OSBPL)</i>, Ankyrin Repeat and Socs Box<i> (ASB)</i>, and Transmembrane Protein<i> (TMEM)</i>,<i> </i>we chose 21 genes that are preferentially expressed in human SkM relative to 52 other tissue types and analyzed relationships between their tissue-specific epigenetics and expression. We also compared their genetics, proteomics, and descriptions in the literature. For this study, we identified genes with little or no previous descriptions of SkM functionality (<i>ASB4</i>,<i> ASB8</i>,<i> ASB10</i>,<i> ASB12</i>,<i> ASB16</i>,<i> LRRC14B</i>,<i> LRRC20</i>,<i> LRRC30</i>, <i>TMEM52</i>,<i> TMEM233</i>, <i>OSBPL6/ORP6</i>,<i> </i>and<i> OSBPL11/ORP11</i>) and included genes whose SkM functions had been previously addressed (<i>ASB2</i>,<i> ASB5</i>,<i> ASB11</i>,<i> ASB15</i>,<i> LRRC2</i>,<i> LRRC38</i>,<i> LRRC39</i>,<i> TMEM38A/TRIC-A</i>, and <i>TMEM38B/TRIC-B</i>). Some of these genes have associations with SkM or heart disease, cancer, bone disease, or other diseases. Among the transcription-related SkM epigenetic features that we identified were: super-enhancers, promoter DNA hypomethylation, lengthening of constitutive low-methylated promoter regions, and SkM-related enhancers for one gene embedded in a neighboring gene (e.g., <i>ASB8-PFKM</i>,<i> LRRC39-DBT</i>, and <i>LRRC14B-PLEKHG4B</i> gene-pairs). In addition, highly or lowly co-expressed long non-coding RNA (lncRNA) genes probably regulate several of these genes. Our findings give insights into tissue-specific epigenetic patterns and functionality of related genes in a gene family and can elucidate normal and disease-related regulation of gene expression in SkM.
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