miR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression

Paul N. Valdmanis (), Hak Kyun Kim, Kirk Chu, Feijie Zhang, Jianpeng Xu, Elizabeth M. Munding, Jia Shen and Mark A. Kay ()
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Paul N. Valdmanis: Stanford University
Hak Kyun Kim: Stanford University
Kirk Chu: Stanford University
Feijie Zhang: Stanford University
Jianpeng Xu: Stanford University
Elizabeth M. Munding: Stanford University
Jia Shen: Stanford University
Mark A. Kay: Stanford University

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07786-7

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