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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylhomocysteinase / genetics
  • Adenosylhomocysteinase / metabolism*
  • Animals
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation
  • DNA Methyltransferase 3B
  • Genome
  • Humans
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Mice
  • Protein Binding
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • S-Adenosylhomocysteine / metabolism

Substances

  • H19 long non-coding RNA
  • Nctc1 lncRNA, mouse
  • RNA, Long Noncoding
  • Insulin-Like Growth Factor II
  • S-Adenosylhomocysteine
  • DNA (Cytosine-5-)-Methyltransferases
  • Adenosylhomocysteinase

Associated data

  • GEO/GSE73014