TCF7L2 Rs290487 Variant Modulates Hepatic Glucose Metabolism Via an Allele-Specific Transcriptional and Chromatin Regulation

Background: TCF7L2 rs290487 C allele increases diabetic risk in Chinese. However, the mechanism remains unclear. We previously demonstrated that donor liver rs290487 C allele brought diabetic risk into liver recipients, indicating a role of rs290487 in hepatic glucose homeostasis.Methods: A total of 195 cirrhotic patients susceptible to hepatogenous diabetes were genotyped. A targeted mutant PLC-PRF-5 cell line was constructed by CRISPR/Cas9 system. ChIP-seq, ATAC-seq, RNA-seq, and metabolomics were performed.Findings: In the clinical cohort, C/C genotype was associated with a higher insulin resistance index and a higher incidence of hepatogenous diabetes as compared to C/T and T/T genotypes. In liver cell lines, cells with C/C genotype (C/C-cells) had enhanced glucose production and decreased glucose uptake, and showed decreased expression of TCF7L2 mRNA and protein content than cells with C/T genotype (C/T-cells). In multi-omics analysis, compared to C/T-cells, C/C cells displayed altered TCF7L2-DNA binding affinity including a specific gain (e.g., PFKP and PPARGC1A) and loss (e.g., PGK1 and PGM1) of some binding sites in glucose metabolism associated genes, which consequently led to an allele-specific transcriptional regulation in metabolic pathways. The differentially expressed genes (e.g., PCK1, G6PC and PPARGC1A) and downstream metabolites (e.g., Oxaloacetate and β-D-Fructose 2,6-bisphosphate) demonstrated an enhanced gluconeogenesis pattern in C/C-cells compared to C/T-cells.Interpretation: TCF7L2 rs290487 variant modulates hepatic glucose metabolism particularly gluconeogenesis via an allele-specific transcription and chromatin regulation.Funding Statement: This study was supported by the National Natural Science Foundation of China (81771713 and 81470892), Zhejiang Provincial Natural Science Foundation of China (LR18H030001 and LY18H120001), and Fundamental Research funds for Central Universities (2019QNA7030).Declaration of Interests: The authors declare that there is no conflict of interest.Ethics Approval Statement: The study was approved by the Ethics Committee and institutional review board at The First Affiliated Hospital, Zhejiang University School of Medicine, and was in accordance with the declaration at Helsinki. Informed consent was obtained from all individuals.