title: H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase.
abstract: DNA methylation is essential for mammalian development and physiology. Here we report that the developmentally regulated H19 lncRNA binds to and inhibits S-adenosylhomocysteine hydrolase (SAHH), the only mammalian enzyme capable of hydrolysing S-adenosylhomocysteine (SAH). SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases that methylate diverse cellular components, including DNA, RNA, proteins, lipids and neurotransmitters. We show that H19 knockdown activates SAHH, leading to increased DNMT3B-mediated methylation of an lncRNA-encoding gene Nctc1 within the Igf2-H19-Nctc1 locus. Genome-wide methylation profiling reveals methylation changes at numerous gene loci consistent with SAHH modulation by H19. Our results uncover an unanticipated regulatory circuit involving broad epigenetic alterations by a single abundantly expressed lncRNA that may underlie gene methylation dynamics of development and diseases and suggest that this mode of regulation may extend to other cellular components.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
authors.forename: Jichun
authors.identifier: http://orcid.org/0000-0002-0727-4034
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Obstetrics and Gynecology, Tianjin Renmin Hospital, Tianjin 300000, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Zhong
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Obstetrics and Gynecology, University Hospital, Bern 3012, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Head and Neck Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Men
authors.affiliation: Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Reproductive Medical Center, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
authors.forename: Juanke
authors.initials: J
authors.lastname: Xie
authors.affiliation: Zymo Research Corporation, Irvine, California 92614, USA.
authors.forename: Karolyn
authors.initials: K
authors.lastname: Giang
authors.affiliation: Zymo Research Corporation, Irvine, California 92614, USA.
authors.forename: Hunter
authors.initials: H
authors.lastname: Chung
authors.affiliation: Zymo Research Corporation, Irvine, California 92614, USA.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Chronic Diseases Epidemiology, Yale School of Public Health, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Lingeng
authors.identifier: http://orcid.org/0000-0001-9871-0809
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Gordon G
authors.initials: GG
authors.lastname: Carmichael
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Taylor
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D043383:Adenosylhomocysteinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D016678:Genome; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D043383:Adenosylhomocysteinase; D004248:DNA (Cytosine-5-)-Methyltransferases; D007335:Insulin-Like Growth Factor II; D062085:RNA, Long Noncoding; D012435:S-Adenosylhomocysteine; D000097584:DNA Methyltransferase 3B; C094335:H19 long non-coding RNA; C584324:Nctc1 lncRNA, mouse