Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development.
Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development.
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microRNA 靶标的全基因组鉴定揭示了肝脏发育过程中 miR-122 对 Hippo 通路的正向调节
DOI：
10.1038/s41419-021-04436-7
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发表时间：
2021-12-14
影响因子：
9
通讯作者：
Qu LH
中科院分区：
文献类型：
--
作者：
Zhang Y;Tan YY;Chen PP;Xu H;Xie SJ;Xu SJ;Li B;Li JH;Liu S;Yang JH;Zhou H;Qu LH
肝脏发育是一个高度复杂的过程，受到表观遗传调节因子、转录因子和 microRNA (miRNA) 精心策划的相互作用的调节。由于肝脏发育过程中所有 miRNA 缺乏全局体内靶标，miRNA 动态控制肝细胞分化的机制仍然难以捉摸。在这里，我们使用 Argonaute (Ago) 高通量测序对不同发育阶段的小鼠肝脏中通过交联免疫沉淀 (HITS-CLIP) 分离的 RNA 进行分析，对大量 Ago 结合 RNA 进行了表征，并获得了肝脏 miRNA-mRNA 相互作用的全基因组图谱。 5个miRNA簇及其潜在靶标的动态变化被确定在特定阶段有差异性参与，在肝脏发育过程中发现了十几个高丰度miRNA及其超级增强子的表观遗传调控。值得注意的是，miR-122 是新生儿和成人肝脏中肝脏特异性且最丰富的 miRNA，通过其靶标组和通路报告基因分析发现它可以调节 Hippo 通路，这对于肝脏大小控制和体内平衡至关重要。从机制上讲，我们进一步证明，miR-122通过直接靶向许多hippo途径调节因子，包括共激活剂TAZ和磷酸酶复合物PPP1CC的关键因子，对Hippo途径转录因子TEAD的结果产生负向调节，PPP1CC有助于YAP（Hippo途径下游的另一种共激活剂）的去磷酸化。这项研究首次鉴定了小鼠肝脏发育过程中的全基因组 miRNA 靶标组，并证明了 miR-122/Hippo 通路以协调方式调节的肝细胞终末分化的新机制。由于 Hippo 通路在细胞增殖和炎症、纤维化和肝细胞癌 (HCC) 等肝脏病理过程中发挥着重要作用，因此我们的研究还可以为 miR-122 在肝脏病理学中的功能提供新的见解。
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.
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影响因子：
8.8
作者：
Alder O;Cullum R;Lee S;Kan AC;Wei W;Yi Y;Garside VC;Bilenky M;Griffith M;Morrissy AS;Robertson GA;Thiessen N;Zhao Y;Chen Q;Pan D;Jones SJM;Marra MA;Hoodless PA
通讯作者：
Hoodless PA
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
29
作者：
Esau, C;Davis, S;Monia, BP
通讯作者：
Monia, BP