Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development
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 co...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04436-7 |
| _version_ | 1798026885482938368 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yin Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T18:42:29Z |
| format | Article |
| id | doaj.art-f52cce88f82c439890189b6219ebea98 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T18:42:29Z |
| publishDate | 2021-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-f52cce88f82c439890189b6219ebea982022-12-22T04:08:57ZengNature Publishing GroupCell Death and Disease2041-48892021-12-01121211210.1038/s41419-021-04436-7Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver developmentYin Zhang0Ye-Ya Tan1Pei-Pei Chen2Hui Xu3Shu-Juan Xie4Shi-Jun Xu5Bin Li6Jun-Hao Li7Shun Liu8Jian-Hua Yang9Hui Zhou10Liang-Hu Qu11MOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityAbstract 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.https://doi.org/10.1038/s41419-021-04436-7 |
| spellingShingle | 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 Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development Cell Death and Disease |
| title | Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development |
| title_full | Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development |
| title_fullStr | Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development |
| title_full_unstemmed | Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development |
| title_short | Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development |
| title_sort | genome wide identification of microrna targets reveals positive regulation of the hippo pathway by mir 122 during liver development |
| url | https://doi.org/10.1038/s41419-021-04436-7 |
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