Back to Search Start Over

Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development

Authors :
Yin Zhang
Ye-Ya Tan
Pei-Pei Chen
Hui Xu
Shu-Juan Xie
Shi-Jun Xu
Bin Li
Jun-Hao Li
Shun Liu
Jian-Hua Yang
Hui Zhou
Liang-Hu Qu
Source :
Cell Death and Disease, Vol 12, Iss 12, Pp 1-12 (2021)
Publication Year :
2021
Publisher :
Nature Publishing Group, 2021.

Abstract

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

Subjects :
Cytology
QH573-671

Details

Language :
English
ISSN :
20414889
Volume :
12
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Cell Death and Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.f52cce88f82c439890189b6219ebea98
Document Type :
article
Full Text :
https://doi.org/10.1038/s41419-021-04436-7