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Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development
- Source :
- Cell Death and Disease, Vol 12, Iss 12, Pp 1-12 (2021), Cell death & disease, vol 12, iss 12, Cell Death & Disease
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group, 2021.
-
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.
- Subjects :
- Cancer Research
Stem Cell Research - Embryonic - Non-Human
Oral and gastrointestinal
Epigenesis, Genetic
Mice
MiR-122
2.1 Biological and endogenous factors
Aetiology
Cancer
Hepatocyte differentiation
Liver Disease
Liver Neoplasms
Argonaute
Cell biology
Differentiation
miRNAs
Argonaute Proteins
Phosphatase complex
Biotechnology
Liver Cancer
Carcinoma, Hepatocellular
1.1 Normal biological development and functioning
Chronic Liver Disease and Cirrhosis
Oncology and Carcinogenesis
Immunology
Biology
Article
Cellular and Molecular Neuroscience
Rare Diseases
Genetic
Underpinning research
Coactivator
Genetics
Animals
Hippo Signaling Pathway
Transcription factor
Hippo signaling pathway
QH573-671
Carcinoma
Human Genome
Hepatocellular
Cell Biology
Stem Cell Research
HITS-CLIP
MicroRNAs
Generic health relevance
Biochemistry and Cell Biology
Digestive Diseases
Cytology
Transcription Factors
Epigenesis
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 12
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....95c6f61b36f430313a4d079a45b7bfb2