{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T15:07:56Z","timestamp":1781276876707,"version":"3.54.1"},"reference-count":93,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS04885"],"award-info":[{"award-number":["NS04885"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epigenomes"],"abstract":"<jats:p>Background\/Objectives: Genome-wide studies of differential DNA methylation often focus on its role in turning transcription on or off. Here we report some atypical epigenetic\/transcription relationships for 92 genes that are highly and preferentially expressed in primary human myoblasts relative to heterologous cell cultures. Methods: We compared methylomes and myoblast-specific differentially methylated regions (DMRs) with methylomes, chromatin profiles, and transcriptomes for many different cell populations. Results: We found that myoblast-associated promoter hypomethylation was unusually prevalent among the 92 myoblast-preferential genes. Sometimes this promoter hypomethylation was seen as a myoblast-associated extension of their constitutively unmethylated region at a CpG island. All 92 genes showed some myoblast-specific hypomethylation, including 32 genes at tissue-specific super-enhancers or broad H3K4-trimethylated promoters. Myoblast hypermethylated DMRs were also associated with almost half of the myoblast-preferential genes. These hypermethylated DMRs were often in intragenic locations embedded in H3K36-trimethylated chromatin in myoblasts. Conclusions: Our analysis suggests that some of the hypermethylated DMRs repress cryptic, alternative, or adjacent promoters. Myoblast hypermethylated DMRs may also downmodulate expression in myoblasts to avoid yet higher RNA levels found in adult or fetal skeletal muscle tissue. The epigenetic insights that were obtained can help elucidate the transcription regulation of some of these genes (e.g., MUSK, RAPSN, HEYL, SYNPO2, SYNPO2L, STAC3, PITX2, and TPPP3) that are implicated in congenital myasthenic syndromes, myasthenia gravis, muscle repair, heart dysfunction, or cancer. This study supports cell type-specific roles for DNA hypo- and hypermethylation as a modulator of transcription levels, in addition to being an on\u2013off switch during differentiation.<\/jats:p>","DOI":"10.3390\/epigenomes10010020","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T09:26:38Z","timestamp":1773393998000},"page":"20","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetics of Genes Displaying High and Preferential Expression in Myoblasts"],"prefix":"10.3390","volume":"10","author":[{"given":"Kenneth C.","family":"Ehrlich","sequence":"first","affiliation":[{"name":"Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Lacey","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Tulane University, New Orleans, LA 70118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1710-0588","authenticated-orcid":false,"given":"Sriharsa","family":"Pradhan","sequence":"additional","affiliation":[{"name":"Genome Biology Division, New England Biolabs, Ipswich, MA 01938, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8187-4476","authenticated-orcid":false,"given":"Melanie","family":"Ehrlich","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Tulane Cancer Center and Hayward Human Genetics Center, Tulane University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.semcdb.2017.11.011","article-title":"Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis","volume":"72","author":"Zammit","year":"2017","journal-title":"Semin. 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