The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r

Abstract

The H19 large intergenic noncoding RNA (lincRNA) is one of the most highly abundant and conserved transcripts in mammalian development, being expressed in both embryonic and extraembryonic cell lineages, yet its physiological function is unknown. Here we show that miR-675, a microRNA (miRNA) embedded within H19’s first exon, is expressed exclusively in the placenta from the gestational time point when placental growth normally ceases, and placentas that lack H19 continue to grow. Overexpression of miR-675 in a range of embryonic and extraembryonic cell lines results in their reduced proliferation; targets of the miRNA are upregulated in the H19 null placenta, including the growth promoting Insulin-like growth factor 1 receptor (Igf1r). Moreover, the excision of miR-675 from H19 is dynamically regulated by the stress response RNA binding protein HuR. These results suggest that H19’s main physiological role is in limiting growth of the placenta prior to birth, by regulated processing of miR-675. The controlled release of miR-675 from H19 may also allow rapid inhibition of cell proliferation in response to cellular stress or oncogenic signals.

Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver–Russell syndrome phenotypes

“…We observed that H19 +/hIC1 placentas not only are smaller, but also have abnormal placental morphology. Although the contribution of an abnormal placenta to fetal growth defects is unclear, it is noteworthy that H19 is more highly expressed in the labyrinthine zone compared with the junctional zone (38), and that Igf2 null mice display a disproportionate reduction in the labyrinthine zone compared with the junctional zone (39). These observations suggest a potential major growth-suppressing effect of increased H19 and silenced Igf2 expression in the labyrinthine zone.…”

Long non-coding RNA-guided regulation in organisms

“…It has been reported that GAS5 RNA serves as a false target of transcription factor GR to prevent the binding of GR to the promoter DNA [28]; an lncRNA derived from the secondary promoter of DHFR can bind in cis the primary promoter to form a DNA-RNA triplet, resulting in blocked recruitment of TFIID, a transcriptional regulation cofactor, to the primary promoter and the subsequent transcription repression [29]; linc-MD1 RNA acts as miRNA sponge to suppress the activities of miR-133 and miR-135, resulting in increased levels of miRNA targets and the ultimate influence on muscle differentiation [30]. In conclusion, the accumulated studies show that lncRNAs not only serve as the precursors of certain small ncRNAs, such as miR-675 encoded by the H19 lncRNA [24,31], but also present a class of regulatory RNAs fundamentally distinct from the small ncRNAs, which appear to play roles through the mechanism of interaction with DNA, RNA or protein.…”

Non-Coding RNAs: A Dynamic and Complex Network of Gene Regulation

“…The ncRNAs as described to be produced by some viruses are hundreds to thousands of nucleotides in length and may have the ability to regulate gene expression in favor of the viral genome [121]. There are examples of long and short ncRNAs intersecting with each other and lncRNAs can themselves be host genes for small RNAs, for example H19 is host to microRNA-675 [122].…”