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Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the <jats:italic>nc886<\/jats:italic> non-coding RNA.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To identify DMRs, we employed the bump hunter method in samples from young (9\u201316\u00a0yr, <jats:italic>n<\/jats:italic>\u2009=\u200992) offspring of women with GDM (O-GDM) and control offspring (<jats:italic>n<\/jats:italic>\u2009=\u200994). Validation by pyrosequencing was performed in an adult offspring cohort (age 28\u201333\u00a0years) consisting of O-GDM (<jats:italic>n<\/jats:italic>\u2009=\u200982), offspring exposed to maternal type 1 diabetes (O-T1D, <jats:italic>n<\/jats:italic>\u2009=\u200967) and control offspring (O-BP, <jats:italic>n<\/jats:italic>\u2009=\u200957). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the <jats:italic>nc886<\/jats:italic>\/<jats:italic>VTRNA2-1<\/jats:italic> non-coding RNA gene. Low methylation status across all CpGs of the <jats:italic>nc886<\/jats:italic> in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue <jats:italic>nc886<\/jats:italic> expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue <jats:italic>nc886<\/jats:italic> expression levels were positively associated with maternal pre-pregnancy BMI (<jats:italic>p<\/jats:italic>\u2009=\u20090.006), but not with the offspring\u2019s own adiposity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our results highlight that <jats:italic>nc886<\/jats:italic> is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of <jats:italic>nc886<\/jats:italic> may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how <jats:italic>nc886<\/jats:italic> regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13148-024-01673-3","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T15:02:18Z","timestamp":1715094138000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy"],"prefix":"10.1186","volume":"16","author":[{"given":"Line","family":"Hjort","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Stokholm","family":"Bredgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Manitta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Marques","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja Elaine","family":"S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Martino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise Groth","family":"Grunnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Kelstrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azadeh","family":"Houshmand-Oeregaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tine Dalsgaard","family":"Clausen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth Reinhardt","family":"Mathiesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sjurdur Frodi","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Saffery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Barr\u00e8s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Damm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan Arthur","family":"Vaag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise Torp","family":"Dalgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,7]]},"reference":[{"issue":"7","key":"1673_CR1","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1007\/s00125-016-3985-5","volume":"59","author":"P Damm","year":"2016","unstructured":"Damm P, Houshmand-Oeregaard A, Kelstrup L, Lauenborg J, Mathiesen ER, Clausen TD. 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Consent from both parents was essential for the participation of the child in the study. All procedures were in accordance with the Declaration of Helsinki II. The clinical follow-up study followed the same procedures with regard to consent and approval of study protocols (H-4\u20132011-045 and H-4-2013-129). The Copenhagen Cohort (CoCo): The protocol was approved by the local ethical committee in Copenhagen and Frederiksberg municipality (KF 11-152\/04 and KF 01-061\/03) and in accordance with the Helsinki declaration. Written as well as oral informed consent was obtained from all participants. The studies are not registered in ClinicalTrials.gov. Both are observational cohorts with no intervention, and at the time of establishment of the cohorts, it was not custom to register such trials.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The manuscript is approved by all authors for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"L.G.G., L.K. and L.T.D. own shares in Novo Nordisk A\/S. A.H.-O. is an employee of Novo Nordisk A\/S and owns shares in the company. After initiation of this work, A.H.-O. became employed by Novo Nordisk A\/S, but Novo Nordisk A\/S was not involved in this project. The remaining authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"61"}}