The role of TCF7L2 rs290487 variant in hepatic glucose metabolism: an integrated analysis of clinical and multi-omics data

TCF7L2 rs290487 C allele increases diabetic risk in Chinese, however the mechanism remains unclear. We herein evaluated the role of rs290487 variant in hepatic glucose homeostasis by integrating clinical and multi-omics data (ChIP-seq, ATAC-seq, RNA-seq, and metabolomics) from CRISPR/Cas9 edited PLC-PRF-5 cell lines (C/C vs. C/T). In clinical cohort, C/C genotype was associated with higher insulin resistance index and higher incidence of hepatogenous diabetes as compared to C/T heterozygote and T/T homozygote genotypes. In liver cell lines, C/C-cells had enhanced glucose production and lower TCF7L2 mRNA and protein levels than C/T-cells. Moreover, C/C-cells presented specific binding affinity of TCF7L2 with genes involving glucose metabolism (e.g., PFKP and PPARGC1A), increased expression of gluconeogenetic genes with specific chromatin openness (e.g., PPARGC1A and HNF4A), and deregulation of metabolites (e.g., ß-D-Fructose 2,6-bisphosphate). In addition, diabetic status (high glucose and insulin) had a more potent effect on TCF7L2 expression than the genetic variant, indicating a significant role of environmental factors on gene expression and disease progression. This study provides a novel mechanism underlying the association between TCF7L2 rs290487 polymorphism and hepatic regulation of glucose homeostasis. Overall design: integrating clinical and multi-omics data (ChIP-seq, ATAC-seq, RNA-seq, and metabolomics) from CRISPR/Cas9 edited PLC-PRF-5 cell lines (C/C vs. C/T)