H19 lncRNA可以结合并抑制S-腺苷高半胱氨酸水解酶.pdf

ARTICLE Received 29 Jun 2015 | Accepted 16 Nov 2015 | Published 21 Dec 2015 DOI: 10.1038/ncomms10221 OPEN H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase 1,2, 1,3, 1,4, 1,5 1,6 7 Jichun Zhou *, Lihua Yang *, Tianyu Zhong *, Martin Mueller , Yi Men , Na Zhang , 1,8 9 9 9 10 7 Juanke Xie , Karolyn Giang , Hunter Chung , Xueguang Sun , Lingeng Lu , Gordon G. Carmichael , Hugh S. Taylor1 Yingqun Huang1 DNA methylation is essential for mammalian development and physiology. Here we report that the developmentally regulated H19 lncRNA binds to and inhibits S-adenosylho- mocysteine 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. 1 Department of Obstetrics, Gynecology, an