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.

中文翻译：

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替代多腺苷酸化调节妊娠糖尿病脂肪组织中代谢和炎症相关蛋白的翻译

在妊娠糖尿病（GDM）中，脂肪组织会出现代谢紊乱和慢性低度炎症。选择性多腺苷酸化 (APA) 是一种转录后修饰机制，可生成具有可变长度 3' 非翻译区 (3'UTR) 的 mRNA，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很好的表征。在这项研究中，我们对对照和 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 Dapars（一种新型 APA 定量算法），我们描绘了脂肪组织的 APA 景观，揭示了 GDM 组中 mRNA 的显着 3'UTR 伸长。大网膜脂肪组织表现出延长的 3'UTR 与代谢和炎症相关基因翻译水平降低之间的显着相关性。 THP-1 衍生巨噬细胞 (TDM) 中的验证实验通过过表达代表性基因 LRRC25 的长和短 3'UTR 亚型，证明了 APA 对翻译水平的影响。此外，LRRC25 经验证可抑制 TDM 中的促炎极化。进一步的探索揭示了 GDM 网膜脂肪组织中两种表达不足的 APA 反式作用因子 CSTF3 和 PPP1CB。总之，本研究提供了对 GDM 脂肪组织 APA 景观的初步见解。 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。这些发现增进了我们对 GDM 相关脂肪组织变化分子机制的理解。