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However, human and animal studies suggest that prenatal metformin exposure may increase the risk of metabolic disorders in adult offspring, yet the underpinning mechanism remains unclear. Here we report that metformin-exposed mouse fetuses exhibit elevated expression of the H19 long noncoding RNA, which induces hypomethylation and increased expression of hepatocyte nuclear factor 4<jats:italic>\u03b1<\/jats:italic> (HNF4<jats:italic>\u03b1<\/jats:italic>). As a transcription factor essential for morphological and functional differentiation of hepatocytes, HNF4<jats:italic>\u03b1<\/jats:italic> also has an indispensable role in the regulation of expression of gluconeogenic genes. Consistently, H19 overexpression in a human liver cell line leads to decreased methylation and increased expression of <jats:italic>Hnf4\u03b1<\/jats:italic>, with concomitant activation of the gluconeogenic program. Mechanistically, we show that the methylation change of <jats:italic>Hnf4\u03b1<\/jats:italic> is induced by H19-mediated regulation of <jats:italic>S<\/jats:italic>-adenosylhomocysteine hydrolase. We also provide evidence that altered H19 expression is a direct effect of metformin in the fetal liver. Our results suggest that metformin from the mother can directly act upon the fetal liver to modify <jats:italic>Hnf4\u03b1<\/jats:italic> expression, a key factor for both liver development and function, and that perturbation of this H19\/Hnf4<jats:italic>\u03b1<\/jats:italic>-mediated pathway may contribute to the fetal origin of adult metabolic abnormalities.<\/jats:p>","DOI":"10.1038\/cddis.2017.392","type":"journal-article","created":{"date-parts":[[2017,12,7]],"date-time":"2017-12-07T13:41:06Z","timestamp":1512654066000},"page":"e3175-e3175","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["H19 lncRNA alters methylation and expression of Hnf4\u03b1 in the liver of metformin-exposed fetuses"],"prefix":"10.1038","volume":"8","author":[{"given":"Jie","family":"Deng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5594-0532","authenticated-orcid":false,"given":"Martin","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramanaiah","family":"Ramillapalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh S","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Paidas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,7]]},"reference":[{"key":"BFcddis2017392_CR1","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.2337\/dc11-1153","volume":"34","author":"DS Feig","year":"2011","unstructured":"Feig DS, Moses RG . 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