Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation
Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation
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DOI：
10.1038/s12276-020-0387-z
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发表时间：
2020-03-10
影响因子：
12.8
通讯作者：
Zhao, Yujun
中科院分区：
文献类型：
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作者：
Wang, Qiang;Liu, Lian;Zhao, Yujun
暴发性肝衰竭（FHF）是指在肝脏正常或代偿性肝病患者中迅速发展为严重急性肝损伤并伴有综合功能受损和脑病的疾病。本研究旨在探讨长链非编码RNA （lncRNA）核富集丰富转录本1 （NEAT1）在FHF肝细胞增殖和凋亡中的作用。我们的研究结果显示，lncRNA NEAT1在d -半乳糖胺(D-GalN)/脂多糖（LPS）诱导的FHF细胞和动物模型中表达上调。lncRNA NEAT1过表达导致肝细胞凋亡升高，大肿瘤抑制激酶2 （large tumor-suppressor kinase 2, LATS2）表达和增殖受损。功能分析显示，lncRNA NEAT1的敲低在体外和体内均能抑制肝细胞凋亡，诱导肝细胞增殖。RNA免疫沉淀和染色质免疫沉淀实验表明，lncRNA NEAT1募集zeste同源物2增强子（EZH2）到LATS2启动子并抑制LATS2的表达。此外，LATS2的异位表达通过调节Hippo/Yes-associated protein （YAP）信号通路增加了肝细胞的增殖并抑制了肝细胞的凋亡。综上所述，我们的研究结果表明lncRNA NEAT1可能作为FHF治疗的新靶点，因为它调节H3K27me3甲基化依赖性促进LATS2。一种不编码蛋白质合成的长链非编码RNA分子与急性肝衰竭（AHF）有关，可能为治疗这种疾病的药物提供新的靶点。AHF可由多种因素诱发，包括病毒、药物、酒精滥用和遗传性状。中国长沙中南大学的程珂、赵玉军及其同事研究了这种名为NEAT1的RNA在AHF细胞和动物模型中的作用。他们发现NEAT1的产生增加，抑制肝细胞增殖并促进肝细胞死亡。他们还揭示了这些作用背后的分子机制细节，其中RNA改变了某些蛋白质的产生和调节修饰。进一步的研究应探讨干扰NEAT1活性的治疗可能性。
Fulminant hepatic failure (FHF) refers to the rapid development of severe acute liver injury with impaired synthetic function and encephalopathy in people with normal liver or well-compensated liver disease. This study aimed to investigate the function of long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) on the proliferation and apoptosis of hepatocytes in FHF. Our results revealed that lncRNA NEAT1 was upregulated in cell and animal models of FHF induced by D-galactosamine (D-GalN)/lipopolysaccharide (LPS). Overexpression of lncRNA NEAT1 resulted in elevated hepatocyte apoptosis and impaired large tumor-suppressor kinase 2 (LATS2) expression and proliferation. Functional analysis revealed that knockdown of lncRNA NEAT1 inhibited hepatocyte apoptosis and induced proliferation both in vitro and in vivo. RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated that lncRNA NEAT1 recruited enhancer of zeste homolog 2 (EZH2) to the LATS2 promoter and repressed LATS2 expression. Furthermore, ectopic expression of LATS2 increased proliferation and inhibited hepatocyte apoptosis by regulating the Hippo/Yes-associated protein (YAP) signaling pathway. Taken together, our findings indicate that lncRNA NEAT1 might serve as a novel target for FHF therapy due to its regulation of H3K27me3 methylation-dependent promotion of LATS2.Liver failure: A NEAT possibility for treatment A long noncoding RNA molecule, one that does not encode the synthesis of protein, is implicated in acute liver failure (AHF) and might offer a new target for drugs to treat the condition. AHF can be induced by various factors, including viruses, drugs, alcohol abuse, and inherited traits. Ke Cheng, Yujun Zhao and colleagues at Central South University in Changsha, China investigated the role of this RNA, called NEAT1, in cell and animal models of AHF. They identified increased production of NEAT1, which suppressed liver cell proliferation and promoted liver cell death. They also uncovered molecular details of the mechanisms underlying these effects, in which the RNA altered the production and regulatory modification of certain proteins. Further research should investigate the therapeutic possibilities of interfering with NEAT1 activity.