Abstract
miR-122 is a highly expressed liver microRNA that is activated perinatally and aids in regulating cholesterol metabolism and promoting terminal differentiation of hepatocytes. Disrupting expression of miR-122 can re-activate embryo-expressed adult-silenced genes, ultimately leading to the development of hepatocellular carcinoma (HCC). Here we interrogate the liver transcriptome at various time points after genomic excision of miR-122 to determine the cellular consequences leading to oncogenesis. Loss of miR-122 leads to specific and progressive increases in expression of imprinted clusters of microRNAs and mRNA transcripts at the Igf2 and Dlk1-Dio3 loci that could be curbed by re-introduction of exogenous miR-122. mRNA targets of other abundant hepatic microRNAs are functionally repressed leading to widespread hepatic transcriptional de-regulation. Together, this reveals a transcriptomic framework for the hepatic response to loss of miR-122 and the outcome on other microRNAs and their cognate gene targets.
Highlights
MicroRNAs mediate site-specific repression of mRNA targets through complementarity base pairing
We found that the 22-nt isoform of miR-122-5p is the first to be generated and the first to be degraded after excision of miR-122 3
In summary, we have identified that when miR-122 expression is abrogated in the adult mouse liver, we can observe a consistent pattern of miR-122-5p isoform degradation. miR-122-5p is processed first through the conversion of the 22-nt isoform to a
Summary
MicroRNAs mediate site-specific repression of mRNA targets through complementarity base pairing. Upon elimination of newly synthesized miR-122, we established the kinetics of miR-122 loss, identified a pathway of processing intermediates for mature miR-122-5p, determined the hepatic microRNAs that are activated in response to miR-122 loss and identified the consequences to mRNAs that are targets of other highly expressed microRNAs in the liver This provides transcriptional responses in the liver leading to HCC. Monouridylation of the 21-nt species (21+U) typically represents ~1.5% of total miR-122-5p reads but increased to 6.7% of miR122 reads by 17 days post-Cre removal and accounted for more reads than the 22-nt isoform at this point (Fig. 1e) The levels of this 21+U species remained constant relative to all microRNA reads for the first 25 days strongly suggesting that this is a degradation intermediate that is continuously replenished until miR-122 is eliminated (Supplementary Figure 1a). Rare hepatocytes that retain expression of miR-122 may exert some selective advantage over their nonexpressing counterparts
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