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Nat Commun. 2015 Dec 21;6:10221. doi: 10.1038/ncomms10221.

H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase.

Author information

1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut 06510, USA.
2
Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
3
Department of Obstetrics and Gynecology, Tianjin Renmin Hospital, Tianjin 300000, China.
4
Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China.
5
Department of Obstetrics and Gynecology, University Hospital, Bern 3012, Switzerland.
6
Department of Head and Neck Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
7
Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
8
Reproductive Medical Center, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
9
Zymo Research Corporation, Irvine, California 92614, USA.
10
Department of Chronic Diseases Epidemiology, Yale School of Public Health, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

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.

PMID:
26687445
PMCID:
PMC4703905
DOI:
10.1038/ncomms10221
[Indexed for MEDLINE]
Free PMC Article
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