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Research Paper|Volume 12, Issue 13|pp 13365—13387

TCF7L2 rs290487 C allele aberrantly enhances hepatic gluconeogenesis through allele-specific changes in transcription and chromatin binding

Xueyou Zhang1, Panpan Ye2, Haitao Huang1, Baohong Wang3,4, Fengqin Dong5, Qi Ling1,3
  • 1Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  • 2Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  • 3Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
  • 4State Key Lab for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  • 5Department of Endocrinology and Metabolism, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
* Equal contribution
Received: February 8, 2020Accepted: May 25, 2020Published: July 10, 2020
https://doi.org/10.18632/aging.103442

Copyright © 2020 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

In this study, we investigated the mechanisms underlying the altered hepatic glucose metabolism and enhanced diabetes risk in individuals with the TCF7L2 rs290487 C allele. Analysis of 195 cirrhotic patients revealed a higher insulin resistance index and incidence of hepatogenous diabetes in patients with the rs290487 C/C genotype compared to those with the C/T or T/T genotype. The in vitro experiments using targeted mutant PLC-PRF-5 cell line showed that cells with the rs290487 C/C genotype (C/C cells) had higher glucose production, lower glucose uptake, and lower TCF7L2 mRNA and protein levels than those with the C/T genotype (C/T cells). Integrated multi-omics analysis of ChIP-seq, ATAC-seq, RNA-seq, and metabolomics data showed genome-wide alterations in the DNA binding affinity of TCF7L2 in the C/C cells, including gain (e.g., PFKP and PPARGC1A) and loss (e.g., PGK1 and PGM1) of binding sites in several glucose metabolism-related genes. These allele-specific changes in transcriptional regulation lead to increased expression of gluconeogenesis-related genes (PCK1, G6PC and PPARGC1A) and their downstream metabolites (oxaloacetate and β-D-fructose 2,6-bisphosphate). These findings demonstrate that the TCF7L2 rs290487 C allele enhances gluconeogenesis through allele-specific changes in transcription and chromatin binding.