The liver specific microRNA-122 modulates hepatic response to infection and inflammation by antagonizing YY1, FoxP3, Nfr1 and E2F4 molecular networks

The liver specific microRNA miR-122 is essential for the maintenance of liver functionality. miR-122 deficient mice develop a pro-inflammatory phenotype in the liver, displaying an increased tendency in developing hepatocellular carcinoma (HCC). miR-122 transcription is regulated by Liver Enriched Transcription Factors (LETF). Transient inhibition of miR-122 activity results in the development of iron deficiency and decreases cholesterol biosynthesis. Expression of miR-122 is dysregulated in a number of human diseases including HCC, viral hepatitis, and NASH. Although a great number of miR-122 targets has been identified and validated, the global set of genes regulated by miR-122 and the actual function of this microRNA are still unknown. Consequently, how miR-122 modulates liver functionality in response to hepatic injury or during liver regeneration is not understood. Here we used polyribosomes fractionation on sucrose gradient in presence of cycloheximide to identify on genome wide level miR-122 target genes and identified that many of these genes are downstream to YY1, FoxP3, E2F4 and Nfr1 transcription factors. Remarkably, we also show that miR-122 transcription is regulated by the activity of the immunoresponsive cytokines TNFα, IL10, BMP6 and TGFβ. This indicates that miR-122 suppression of its targets is crucial in modulating the response of liver cells to infection and inflammation.

Corresponding author: Castoldi, Mirco

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