Li Qinjin, Pan Yanyan, Zhang Jing, Hu Boxu, Qin Dan, Liu Shenghui, Chen Ning, Zhang Lisheng
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
iScience. 2024 Feb 20;27(3):109278. doi: 10.1016/j.isci.2024.109278. eCollection 2024 Mar 15.
Epigenetic modifications have emerged as key regulators of metabolism-related complex diseases including the alcoholic fatty liver disease (AFLD) prevalent chronic liver disorder with significant economic implications. Building upon previous research that emphasizes ten-eleven translocation (TET) proteins' involvement in adipocyte insulin sensitization and fatty acid oxidation, we explored the role of TET2 protein in AFLD pathogenesis which catalyzes 5-methylcytosine into 5-hydroxymethylcytosine in DNA/RNA. Our findings revealed that TET2 deficiency exacerbates AFLD progression. And TET2 influenced the expression and activity of sterol regulatory element binding protein 1 (SREBP1), a key regulator of hepatic lipid synthesis, by modulating mRNA retention. Employing RIP-qPCR and bisulfite sequencing techniques, we provided evidence of TET2-mediated epigenetic modifications on mRNA, thereby affecting lipid metabolism. Through elucidating the role of methylation in RNA nuclear retention via paraspeckles, our study enhances understanding of AFLD pathogenesis from an epigenetic perspective, paving the way for identifying potential therapeutic targets.
表观遗传修饰已成为代谢相关复杂疾病的关键调节因子，包括酒精性脂肪肝病（AFLD），这是一种普遍存在的慢性肝脏疾病，具有重大的经济影响。基于先前强调十 - 十一易位（TET）蛋白参与脂肪细胞胰岛素敏感性和脂肪酸氧化的研究，我们探索了TET2蛋白在AFLD发病机制中的作用，TET2蛋白可催化DNA/RNA中的5 - 甲基胞嘧啶转化为5 - 羟甲基胞嘧啶。我们的研究结果表明，TET2缺乏会加剧AFLD的进展。并且TET2通过调节mRNA保留来影响肝脏脂质合成的关键调节因子甾醇调节元件结合蛋白1（SREBP1）的表达和活性。通过采用RIP - qPCR和亚硫酸氢盐测序技术，我们提供了TET2介导的mRNA表观遗传修饰的证据，从而影响脂质代谢。通过阐明甲基化在通过旁斑的RNA核保留中的作用，我们的研究从表观遗传学角度增强了对AFLD发病机制的理解，为确定潜在的治疗靶点铺平了道路。
