Aging increases susceptibility to liver fibrosis through enhanced NAT10-mediated ac4C modification of TGFβ1 mRNA.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Xuyun Peng, Panlong Li, Ying Zhang, Qi Zhang, Weicheng Liang
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引用次数: 0

Abstract

Background: The epidemiological observational studies unveiled that aging is one of the risk factors for liver fibrosis, and the hepatic tissues in the elderly harbor more fibrotic lesions when compared to those in young people. Previous investigations found that TGFβ1 was elevated with aging and promoted liver fibrosis. However, the underlying mechanisms of aging and liver fibrosis remain largely unknown.

Methods: CCl4-induced liver fibrosis animal models were used in this study. The impact of NAT10 on liver fibrosis and cellular senescence was analyzed by using NAT10 overexpression or knockout hepatic stellate cell lines. The distribution of ac4C RNA modification was monitored by the acRIP-seq. The RNA-protein interaction was examined by the RNA immunoprecipitation.

Results: We demonstrated that the middle-aged mice were more susceptible to the CCl4-induced liver fibrosis when compared to the young mice. Then, we found that RNA ac4C-modifying enzyme NAT10 was transcriptionally activated by TGFβ1/SMAD2/3 axis and highly expressed in the aging liver as well as liver fibrosis mouse model. Suppression of NAT10 by its inhibitor Remodelin or specific shRNA attenuated senescence and activation of hepatic stellate cells. Subsequent studies found that NAT10 directly triggered the ac4C RNA modification of TGFβ1 mRNA by physically interacting with the RNA-binding protein PTBP1, enhancing the stabilization of TGFβ1 mRNA and subsequent activation of TGFβ/SMAD signaling pathway. Animal studies demonstrated that inhibition of NAT10 by Remodelin significantly alleviated liver fibrosis and cellular senescence.

Conclusions: Our study identified a previously unknown mechanism of how TGFβ1 drives cellular senescence and liver fibrosis through NAT10-mediated ac4C mRNA modification.

衰老通过增强nat10介导的tgf - β1 mRNA的ac4C修饰增加肝纤维化易感性。
背景:流行病学观察研究表明,衰老是肝纤维化的危险因素之一,老年人肝组织中纤维化病变比年轻人多。先前的研究发现,tgf - β1随着年龄的增长而升高,并促进肝纤维化。然而,衰老和肝纤维化的潜在机制在很大程度上仍然未知。方法:采用ccl4诱导肝纤维化动物模型。通过NAT10过表达或敲除肝星状细胞株,分析NAT10对肝纤维化和细胞衰老的影响。ac4C RNA修饰分布通过acrp -seq监测。RNA免疫沉淀法检测RNA-蛋白相互作用。结果:我们证明了中年小鼠比年轻小鼠更容易发生ccl4诱导的肝纤维化。然后,我们发现RNA ac4c修饰酶NAT10被tgf - β1/SMAD2/3轴转录激活,并在衰老肝脏和肝纤维化小鼠模型中高表达。通过其抑制剂重塑蛋白或特异性shRNA抑制NAT10可减轻肝星状细胞的衰老和活化。后续研究发现,NAT10通过与RNA结合蛋白PTBP1的物理相互作用,直接触发tgf - β1 mRNA的ac4C RNA修饰,增强tgf - β1 mRNA的稳定性,进而激活tgf - β/SMAD信号通路。动物实验表明,重塑蛋白抑制NAT10可显著减轻肝纤维化和细胞衰老。结论:我们的研究确定了TGFβ1如何通过nat10介导的ac4C mRNA修饰驱动细胞衰老和肝纤维化的未知机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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