Jiao Wang, Feng Guo, Lina Wu, Qian Qin, Jiao Wang, Fengjiao Huang, Shengnan Ma, Haibin Wang, Xinyi Dou, Jingwei Xing, Shoujun Wang
METTL14‑dependent m6A deposition safeguards lncRNA Gm2824 integrity, enabling it to serve as a molecular scaffold that recruits YBX1 to activate Foxa1‑mediated GLP‑1 generation. Disruption of this epitranscriptomic circuit under hyperglycemic stress contributes to the incretin insufficiency characteristic of T2DM.
OBJECTIVE: Attenuated endogenous secretion of glucagon‑like peptide‑1 (GLP‑1) is a defining feature of type 2 diabetes mellitus (T2DM), yet the precise molecular circuitry underpinning this defect remains obscure. Here, we delineate how METTL14‑driven N6‑methyladenosine (m6A) marking of the long noncoding RNA (lncRNA) Gm2824 modulates GLP‑1 output through the YBX1/Foxa1 signaling cascade.
METHODS: Murine enteroendocrine STC‑1 cells were challenged with high‑glucose (HG) conditions to emulate the diabetic milieu. Transcriptional abundance and m6A decoration of Gm2824 were quantified via qPCR and MeRIP‑qPCR. Molecular engagement between Gm2824, YBX1, and the Foxa1 promoter was interrogated using RNA pull‑down, RNA immunoprecipitation (RIP), and dual‑luciferase assays. Complementary in vivo analyses employed Gm2824 knockout and knock‑in mouse models with experimental T2DM to monitor metabolic homeostasis and incretin signaling dynamics.
RESULTS: Sustained hyperglycemia suppressed METTL14 expression, leading to diminished m6A modification and compromised stability of Gm2824. This lncRNA physically associates with YBX1, fostering its nuclear import and promoter occupancy at Foxa1, thereby amplifying Foxa1 transcriptional activity. Elevated Foxa1 subsequently drives Pcsk1 expression, augmenting GLP‑1 maturation. Ablation of Gm2824 disrupted the YBX1/Foxa1 axis, blunting GLP‑1 release and aggravating hyperglycemia. In contrast, enforced Gm2824 expression reinstated GLP‑1 biosynthesis and normalized glycemic control in diabetic mice-a rescue effect nullified by YBX1 depletion.
CONCLUSION: METTL14‑dependent m6A deposition safeguards lncRNA Gm2824 integrity, enabling it to serve as a molecular scaffold that recruits YBX1 to activate Foxa1‑mediated GLP‑1 generation. Disruption of this epitranscriptomic circuit under hyperglycemic stress contributes to the incretin insufficiency characteristic of T2DM.