Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease.
Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease.
复制标题
DOI：
10.1093/nar/gkac165
复制
发表时间：
2022-04-08
影响因子：
14.9
通讯作者：
Vernia S
中科院分区：
文献类型：
--
作者：
Jobbins AM;Haberman N;Artigas N;Amourda C;Paterson HAB;Yu S;Blackford SJI;Montoya A;Dore M;Wang YF;Sardini A;Cebola I;Zuber J;Rashid ST;Lenhard B;Vernia S
前体mRNA加工是真核细胞产生成熟mRNA和调控基因表达的重要机制。虽然前体mRNA加工缺陷与许多疾病有关，但其在代谢病理学中的参与仍不清楚。在这里，我们表明，选择性剪接和选择性多聚腺苷酸化，前mRNA加工的两个主要步骤，在非酒精性脂肪肝（NAFLD）显着改变。此外，我们发现富含丝氨酸和精氨酸的剪接因子10（SRSF10）结合在共识多聚腺苷酸化基序附近富集，并且其表达在NAFLD中显著降低，表明在这种情况下介导前mRNA失调的作用。一致地，在体外小鼠和人肝细胞中以及在体内小鼠肝脏中，发现SRSF10的失活使关键代谢基因（如过氧化物酶体增殖物激活受体α（PPARA））的多聚腺苷酸化失调，并加剧饮食诱导的代谢功能障碍。总的来说，我们的工作涉及在肥胖诱导的肝脏疾病中失调的前mRNA聚腺苷酸化，并揭示了SRSF10在这一过程中的新作用。
Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process.
登录
查看更多内容
影响因子：
14.9
作者：
Arhin, GK;Boots, M;Wilusz, J
通讯作者：
Wilusz, J
DOI：
10.1038/nrm.2017.27
发表时间：
2017-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baralle FE;Giudice J
通讯作者：
Giudice J
影响因子：
16
作者：
Gunderson, SI;Polycarpou-Schwarz, M;Mattaj, IW
通讯作者：
Mattaj, IW
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
29
作者：
Batista TM;Jayavelu AK;Wewer Albrechtsen NJ;Iovino S;Lebastchi J;Pan H;Dreyfuss JM;Krook A;Zierath JR;Mann M;Kahn CR
通讯作者：
Kahn CR