The liver specific microRNA-122 modulates hepatic response to infection and inflammation by antagonizing YY1, FoxP3, Nrf1 and E2F4 molecular networks

Introduction:

Since their discovery, microRNAs (miRNAs) have changed our understanding of the regulation and fine-tuning of mRNA translation. One prominent member of this family is the liver-specific miRNA-122. miR-122 regulates many aspects of liver physiology including hepatocyte differentiation, cholesterol biosynthesis and systemic iron homeostasis. Importantly, deregulation of miR-122 expression has been reported in nearly every pathological condition of the liver, including chronic inflammation, viral infection, fibrosis and hepatocellular carcinomas. Although being one of the most characterized miRNAs, little is still known about the upstream pathways involved in miR-122 modulation or gene networks downstream to miR-122. This work had two specific aims: i) to identify and characterize the promoter region of human MIR122, with a focus on the link between miR-122 dysregulation and biogenesis of liver diseases and: ii) to unravel the molecular networks that are fine-tuned by this miRNA.

Results:

Bioinformatic analyses show that MIR122 core promoter is evolutionary conserved across different species and that human MIR122 promoter is enriched for potential transcription factor binding sites (e.g. for Smad4, NFκB or STAT). Reporter gene assays confirm the responsiveness of the human MIR122 promoter region to disease-associated cytokines. TGFβ was found to downregulate the activity of the promoter, whereas TNFα and IL10 were found to activate the promoter. Transcriptomic analysis on polysomal fractions and proteomic analysis carried out on human hepatoma cell lines overexpressing miR-122 provides insight into the regulatory networks downstream to this miRNA. Our data suggests that miR-122 antagonizes the activity of the transcription factors FoxP3, Nrf1, E2F4 and YY1, which in turn have been associated to chronic liver diseases and malignancies.

Discussion:

Altogether our data provides insights into the physiological role of miR-122 in the liver, strengthening the hypothesis that miR-122 responds to and modulates the molecular effects in liver disease.