The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs

Abstract

SUMMARY Abundantly expressed in fetal tissues and adult muscle, the developmentally regulated H19 long noncoding RNA (lncRNA) has been implicated in human genetic disorders and cancer. However, how H19 acts to regulate gene function has remained enigmatic, despite the recent implication of its encoded miR675 in limiting placental growth. We noted that vertebrate H19 harbors both canonical and noncanonical binding sites for the let-7 family of microRNAs, which plays important roles in development, cancer, and metabolism. Using H19 knockdown and overexpression, combined with in vivo crosslinking and genome-wide transcriptome analysis, we demonstrate that H19 modulates let-7 availability by acting as a molecular sponge. The physiological significance of this interaction is highlighted in culture where H19 depletion causes precocious muscle differentiation, a phenotype recapitulated by let-7 overexpression. Our results reveal an unexpected mode of action of H19 and identify this lncRNA as an important regulator of the major let-7 family of microRNAs.

The long intergenic non-coding RNA CCR492 functions as a let-7 competitive endogenous RNA to regulate c-Myc expression

“…Indeed this is accomplished by the expression of non-coding RNAs containing multiple MREs. In humans, the lncRNA H19 functions as a sponge to antagonize let-7 to regulate muscle differentiation [24]. We here reported a different lincRNA that is not conserved hence performs the same function of inhibiting let-7 activity in mouse in a different cellular context.…”

“…In the cytoplasm, lncRNAs have been proposed to function as ceRNAs to modulate the availability of miRNAs, sequestering them from their protein coding target RNAs [19]. In agreement with this model, a number of transcripts that act as potential ceRNAs have been identified in different cellular contexts [20][21][22][23][24]. Inspection of CCR492 sequence revealed the presence of 4 high-affinity recognition elements for the let-7 family of miRNAs, which are known to be involved in the control of the cell cycle [10] suggesting that CCR492 could function as a sponge for let-7…”

ARHGAP42 promotes cell migration and invasion involving PI3K/Akt signaling pathway in nasopharyngeal carcinoma

“…One example is H19, which is expressed at high levels in a human NPC cell line. H19 plays an important role in NPC cell differentiation and transcriptional silencing of imprinted genes 22, 23. The expression of antisense lncRNA has been shown to be correlated with repression in cis of protein‐coding genes.…”

Sequencing and characterization of lncRNAs in the breast muscle of Gushi and Arbor Acres chickens

“…lncRNA H19 acts as a molecular sponge for the major let-7 family of miRNAs, establishing a role for the H19/let-7 axis in myogenic differentiation. H19 depletion causes D r a f t precocious muscle differentiation, a phenotype that is recapitulated by let-7 overexpression (Kallen et al 2013). In addition, H19 has a trans-regulatory function in promoting skeletal muscle differentiation and regeneration that is mediated by embedded microRNAs (Dey et al 2014).…”