Chen Bingnan, Chen Xuyang, Hu Ruohan, Li Hongli, Wang Min, Zhou Linwei, Chen Hao, Wang Jianqi, Zhang Hanwen, Zhou Xiaobo, Zhang Hua
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, China.
Comput Struct Biotechnol J. 2024 Mar 15;23:1298-1310. doi: 10.1016/j.csbj.2024.03.013. eCollection 2024 Dec.
In gestational diabetes mellitus (GDM), adipose tissue undergoes metabolic disturbances and chronic low-grade inflammation. Alternative polyadenylation (APA) is a post-transcriptional modification mechanism that generates mRNA with variable lengths of 3' untranslated regions (3'UTR), and it is associated with inflammation and metabolism. However, the role of APA in GDM adipose tissue has not been well characterized. In this study, we conducted transcriptomic and proteomic sequencing on subcutaneous and omental adipose tissues from both control and GDM patients. Using Dapars, a novel APA quantitative algorithm, we delineated the APA landscape of adipose tissue, revealing significant 3'UTR elongation of mRNAs in the GDM group. Omental adipose tissue exhibited a significant correlation between elongated 3'UTRs and reduced translation levels of genes related to metabolism and inflammation. Validation experiments in THP-1 derived macrophages (TDMs) demonstrated the impact of APA on translation levels by overexpressing long and short 3'UTR isoforms of a representative gene LRRC25. Additionally, LRRC25 was validated to suppress proinflammatory polarization in TDMs. Further exploration revealed two underexpressed APA trans-acting factors, CSTF3 and PPP1CB, in GDM omental adipose tissue. In conclusion, this study provides preliminary insights into the APA landscape of GDM adipose tissue. Reduced APA regulation in GDM omental adipose tissue may contribute to metabolic disorders and inflammation by downregulating gene translation levels. These findings advance our understanding of the molecular mechanisms underlying GDM-associated adipose tissue changes.
在妊娠期糖尿病（GDM）中，脂肪组织会发生代谢紊乱和慢性低度炎症。可变聚腺苷酸化（APA）是一种转录后修饰机制，可产生具有不同长度3'非翻译区（3'UTR）的mRNA，并且与炎症和代谢相关。然而，APA在GDM脂肪组织中的作用尚未得到充分表征。在本研究中，我们对对照组和GDM患者的皮下和网膜脂肪组织进行了转录组和蛋白质组测序。使用一种新型的APA定量算法Dapars，我们描绘了脂肪组织的APA图谱，揭示了GDM组中mRNA的3'UTR显著延长。网膜脂肪组织中延长的3'UTR与代谢和炎症相关基因的翻译水平降低之间存在显著相关性。在THP-1衍生的巨噬细胞（TDM）中的验证实验通过过表达代表性基因LRRC25的长和短3'UTR异构体证明了APA对翻译水平的影响。此外，LRRC25被验证可抑制TDM中的促炎极化。进一步探索发现GDM网膜脂肪组织中有两个表达不足的APA反式作用因子CSTF3和PPP1CB。总之，本研究为GDM脂肪组织的APA图谱提供了初步见解。GDM网膜脂肪组织中APA调节的减少可能通过下调基因翻译水平导致代谢紊乱和炎症。这些发现推进了我们对GDM相关脂肪组织变化潜在分子机制的理解。
