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.

LncRNA H19 confers chemoresistance in ERα-positive breast cancer through epigenetic silencing of the pro-apoptotic gene BIK

“…Our research has revealed that high expression of H19 in breast cancer attenuates cell apoptosis normally seen in response to chemotherapy. Other studies have reported that H19 promotes the progression and metastasis of tumors in different ways, by serving as a miRNA sponge, by altering DNA methylation, and by controlling mRNA decay [10, 18, 19]. In the present paper, we have demonstrated an epigenetic inhibition of pro-apoptotic gene BIK by the association of H19 with the histone methyltransferase EZH2.…”

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction

“…iLet7s are chemically modified oligonucleotides that specifically bind to let-7 and inhibit its activity. The rationale for including iLet7 was to confirm the contribution of let-7 to the H19-mediated pathway, as H19 has other functions besides sequestering let-7 [10–13, 23]. Thus, in the presence of iLet7, we would expect that the effects of H19 knockdown on EVT would be attenuated, as iLet7 would neutralize let-7 released from H19 sequestration.…”

“…The incomplete restoration of TβR3 expression by iLet7 was not surprising given that H19 is a multifunctional lncRNA. We have recently reported that H19 alters gene methylation genome-wide through modulation of the S-adenosylhomocysteine hydrolase activity [23], including H19 knockdown-induced hypomethylation of TβR3 in the intron region [23]. It remains to be tested whether downregulation of H19 in human trophoblast cells might induce methylation changes in the TβR3 gene, which may explain the partial restoration of TβR3 expression by iLet7.…”

H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer

“…Studies on H19 function in cancer show both oncogenic and tumor suppressive effects (Medrzycki et al, 2014, Barsyte-Lovejoy et al, 2006, Hao et al, 1993, Juan et al, 2000). The reported H19 activities are diverse, including interaction with epigenetic regulators (Monnier et al, 2013, Giovarelli et al, 2014, Zhou et al, 2015, Luo et al, 2013), regulation of microRNAs as competing endogenous RNA (ceRNA) (Yan et al, 2015, Imig et al, 2015, Kallen et al, 2013, Liang et al, 2015), or production of miR-675 as a primary transcript (Keniry et al, 2012, Venkatraman et al, 2013, Zhu et al, 2014, Shi et al, 2014, Tsang et al, 2010). …”