{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T14:54:43Z","timestamp":1779375283005,"version":"3.53.1"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2016,4,28]],"date-time":"2016-04-28T00:00:00Z","timestamp":1461801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2016,4,28]],"date-time":"2016-04-28T00:00:00Z","timestamp":1461801600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:p>DNA methyltransferase 1 (DNMT1) is an essential regulator maintaining both epigenetic reprogramming during DNA replication and genome stability. We investigated the role of DNMT1 in the regulation of postnatal liver histogenesis under homeostasis and stress conditions. We generated <jats:italic toggle=\"yes\">Dnmt1<\/jats:italic> conditional knockout mice (<jats:italic toggle=\"yes\">Dnmt1\u0394alb\n                           <\/jats:italic>) by crossing <jats:italic toggle=\"yes\">Dnmt1fl\/fl\n                           <\/jats:italic> with albumin\u2010cyclization recombination transgenic mice. Serum, liver tissues, and primary hepatocytes were collected from 1\u2010week\u2010old to 20\u2010week old mice. The <jats:italic toggle=\"yes\">Dnmt1\u0394alb\n                           <\/jats:italic> phenotype was assessed by histology, confocal and electron microscopy, biochemistry, as well as transcriptome and methylation profiling. Regenerative growth was induced by partial hepatectomy and exposure to carbon tetrachloride. The impact of <jats:italic toggle=\"yes\">Dnmt1<\/jats:italic> knockdown was also analyzed in hepatic progenitor cell lines; proliferation, apoptosis, DNA damage, and sphere formation were assessed. <jats:italic toggle=\"yes\">Dnmt1<\/jats:italic> loss in postnatal hepatocytes caused global hypomethylation, enhanced DNA damage response, and initiated a senescence state causing a progressive inability to maintain tissue homeostasis and proliferate in response to injury. The liver regenerated through activation and repopulation from progenitors due to lineage\u2010dependent differences in albumin\u2010cyclization recombination expression, providing a basis for selection of less mature and therefore less damaged hepatic progenitor cell progeny. Consistently, efficient knockdown of <jats:italic toggle=\"yes\">Dnmt1<\/jats:italic> in cultured hepatic progenitor cells caused severe DNA damage, cell cycle arrest, senescence, and cell death. <jats:italic toggle=\"yes\">Mx1\u2010<\/jats:italic>cyclization recombination\u2010driven deletion of <jats:italic toggle=\"yes\">Dnmt1<\/jats:italic> in adult quiescent hepatocytes did not affect liver homeostasis. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: These results establish the indispensable role of DNMT1\u2010mediated epigenetic regulation in postnatal liver growth and regeneration; <jats:italic toggle=\"yes\">Dnmt1\u0394alb\n                           <\/jats:italic> mice provide a unique experimental model to study the role of senescence and the contribution of progenitor cells to physiological and regenerative liver growth. (H<jats:sc>epatology<\/jats:sc> 2016;64:582\u2010598)<\/jats:p>","DOI":"10.1002\/hep.28563","type":"journal-article","created":{"date-parts":[[2016,3,22]],"date-time":"2016-03-22T05:34:50Z","timestamp":1458624890000},"page":"582-598","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":56,"title":["DNMT1 is a required genomic regulator for murine liver histogenesis and regeneration"],"prefix":"10.1097","volume":"64","author":[{"given":"Kosuke","family":"Kaji","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina M.","family":"Factor","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper B.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD"},{"name":"Biotech Research and Innovation Centre,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian E.","family":"Durkin","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Tomokuni","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens U.","family":"Marquardt","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD"},{"name":"Department of Medicine I,Johannes Gutenberg University of Mainz,Mainz,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias S.","family":"Matter","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Hoang","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis,Center for Cancer Research,National Cancer Institute,National Institutes of 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