Abstract
Liver development is a highly complex process that is regulated by the orchestrated interplay of epigenetic regulators, transcription factors, and microRNAs (miRNAs). Owing to the lack of global in vivo targets of all miRNAs during liver development, the mechanisms underlying the dynamic control of hepatocyte differentiation by miRNAs remain elusive. Here, using Argonaute (Ago) high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) in the mouse liver at different developmental stages, we characterized massive Ago-binding RNAs and obtained a genome-wide map of liver miRNA-mRNA interactions. The dynamic changes of five clusters of miRNAs and their potential targets were identified to be differentially involved at specific stages, a dozen of high abundant miRNAs and their epigenetic regulation by super-enhancer were found during liver development. Remarkably, miR-122, a liver-specific and most abundant miRNA in newborn and adult livers, was found by its targetome and pathway reporter analyses to regulate the Hippo pathway, which is crucial for liver size control and homeostasis. Mechanistically, we further demonstrated that miR-122 negatively regulates the outcomes of the Hippo pathway transcription factor TEAD by directly targeting a number of hippo pathway regulators, including the coactivator TAZ and a key factor of the phosphatase complex PPP1CC, which contributes to the dephosphorylation of YAP, another coactivator downstream of the Hippo pathway. This study identifies for the first time the genome-wide miRNA targetomes during mouse liver development and demonstrates a novel mechanism of terminal differentiation of hepatocytes regulated by the miR-122/Hippo pathway in a coordinated manner. As the Hippo pathway plays important roles in cell proliferation and liver pathological processes like inflammation, fibrosis, and hepatocellular carcinoma (HCC), our study could also provide a new insight into the function of miR-122 in liver pathology.
Highlights
The liver is a highly organized structure formed by the interaction of many cells and tissues
This study identifies for the first time the genome-wide miRNA targetomes during mouse liver development and demonstrates a novel mechanism of terminal differentiation of hepatocytes regulated by the miR-122/Hippo pathway in a coordinated manner
By integrating analysis of the targetome obtained by AGO HITS-CLIP and pathway reporter assays, our analysis reveals a new function of miR-122, which serves as a key regulator of the Hippo pathway
Summary
The liver is a highly organized structure formed by the interaction of many cells and tissues. The coordinated (Cluster III), P7 (Cluster IV), and adult liver (Cluster V) were dynamic change in Hippo signaling and miRNAs, as well as the identified (Table S3) This profile implies that several hundred regulation of the pathway activity by miRNAs during liver miRNAs, regardless of their abundance, are differentially involved development, is a very interesting question to explore. We conducted Ago HITS-CLIP and performed high abundant miRNAs in clusters IV and V [14, 22, 23], were genome-wide identification of miRNA targets of the mouse liver at promptly upregulated during development and reached a different developmental stages. The H3K27ac signals of hematopoiesis-related miRNAs miR-142
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