The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298551 | GEO | 2025/08/06
REPOSITORIES: GEO
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Project description:Background and Aims: The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we used multimodal single nuclei genomics techniques to examine the spatial transcriptional function of the transcription factor 7-like 2 (TCF7L2) in rodent liver. We also determined whether inactivation of TCF7L2 disrupted the normal metabolic architecture of the liver and influenced the development of fibrotic liver diseases. Methods: Multimodal single nuclei RNA- and ATAC-Seq were used to examine the spatial expression and DNA binding activity of TCF7L2 across the liver lobule. The transcriptional activity of TCF7L2 was targeted by removing exon 11 of Tcf7l2, which encodes part of the DNA binding domain (DBD). The effect of TCF7L2 inactivation on transcriptional regulators of zonation, hepatic metabolism, and the development of fibrosis was investigated in Hep-TCF7L2ΔDBD mice fed the Gubra Amylin Nash (GAN) or choline-deficient amino acid-defined high fat (CDAHFD) diet for 24- and 8-weeks, respectively. Results: Tcf7l2 mRNA expression was ubiquitous across the liver lobule, but the presence of the consensus TCF/LEF DNA binding motif in open chromatin was enriched in pericentral (PC) hepatocytes in zone 3, but not periportal (PP) or mid-lobular hepatocytes in zones 1 and 2. Consistent with this, PC hepatocyte gene expression was lost in Hep-TCF7L2ΔDBD mice, which we link to alterations in the transcriptional activity of zonal repressors Tbx3 and Tcf7l1. The absence of PC hepatocyte gene expression resulted in impaired bile acid synthesis and hepatic cholesterol accumulation, and disrupted metabolic pathways linked to ammonia detoxification, most notably glutamine/glutamate homeostasis. Following the CDAHFD, Hep-TCF7L2ΔDBD mice developed more severe hepatic fibrosis. Finally, TCF7L2 expression declined in human livers as the severity of fibrosis progressed. Conclusion: TCF7L2 is an important transcriptional regulator of PC hepatocytes in zone 3, and regulates multiple zonated metabolic pathways that may contribute to the development of fibrotic liver diseases.
2025-01-08 | GSE239480 | GEO
Project description:Most studies on TCF7L2 SNP variants in the pathogenesis of type 2 diabetes (T2D) focus on a role of the encoded transcription factor TCF4 in β-cells. Here, a mouse genetics approach shows that removal of TCF4 from β-cells does not affect their function, while manipulating TCF4 levels in the liver has major effects on metabolism. In Tcf7l2-/- mice, the immediate postnatal surge in liver metabolism does not occur. Consequently, pups die due to hypoglycemia. Combining chromatin immunoprecipitation with gene expression profiling, we identify a TCF4-controlled metabolic gene program that is acutely activated in the postnatal liver. In concordance, adult liver-specific Tcf7l2 knockout mice show reduced hepatic glucose production during fasting and display improved glucose homeostasis when maintained on high-fat diet. Furthermore, liver-specific TCF4 overexpression increases hepatic glucose production. These observations imply that TCF4 directly activates metabolic genes, and that inhibition of Wnt signaling may be beneficial in metabolic disease. RNA was extracted from liver tissues of the Tcf7l2 wildtype or knockout mice with treatments as indicated. Microarray analysis was performed to compare the expression profile changes between Tcf7l2 knockout and wildtype mice in response to treatment.
2012-11-01 | E-GEOD-41284 | biostudies-arrayexpress
Project description:Most studies on TCF7L2 SNP variants in the pathogenesis of type 2 diabetes (T2D) focus on a role of the encoded transcription factor TCF4 in β-cells. Here, a mouse genetics approach shows that removal of TCF4 from β-cells does not affect their function, while manipulating TCF4 levels in the liver has major effects on metabolism. In Tcf7l2-/- mice, the immediate postnatal surge in liver metabolism does not occur. Consequently, pups die due to hypoglycemia. Combining chromatin immunoprecipitation with gene expression profiling, we identify a TCF4-controlled metabolic gene program that is acutely activated in the postnatal liver. In concordance, adult liver-specific Tcf7l2 knockout mice show reduced hepatic glucose production during fasting and display improved glucose homeostasis when maintained on high-fat diet. Furthermore, liver-specific TCF4 overexpression increases hepatic glucose production. These observations imply that TCF4 directly activates metabolic genes, and that inhibition of Wnt signaling may be beneficial in metabolic disease.
2012-11-01 | GSE41284 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) associated with type 2 diabetes (T2D) easily progresses toward severe forms of nonalcoholic steatohepatitis (NASH) and fibrosis, and the underlying mechanism is under active investigation. Here, we established the role of transcription factor 7-like 2 (TCF7L2), the most significant T2D susceptibility gene, in NAFLD development and progression. Hepatic TCF7L2 expression was decreased in liver biopsies of patients with NAFLD. Based on the major risk factors for NAFLD development, liver-specific TCF7L2 knockout mice were subjected to a high-fat diet providing fatty acids (FAs) and refeeding/high-carbohydrate diet stimulating de novo lipogenesis. Hepatic TCF7L2 deficiency significantly increased the lipid synthetic pathways and hepatic TG accumulation by preferentially metabolizing carbohydrates than FAs. Mechanistically, TCF7L2 regulated miRNAs targeting SREBF1c and enhanced proteasome-mediated MLXIPL (ChREBP) degradation. Our findings will deepen the pathophysiological mechanism of NAFLD associated with dietary carbohydrate and diabetes, and will provide a potential target for treatment of NAFLD.
2023-01-09 | GSE162449 | GEO
Project description:TCF7L2 is one of the strongest type 2 diabetes (T2DM) candidate genes to emerge from GWAS studies, but the mechanisms by which it regulates the pathways which are important in the pathogenesis of type 2 diabetes are unknown. Previous in vitro and in vivo studies have focused on the link between TCF7L2 and insulin secretion as an explanation for the association between TCF7L2 and T2DM. However, TCF7L2 and the Wnt/β-catenin pathway are important for metabolic zonation in the liver. This raises the interesting possibility that TCF7L2 may influence glucose homeostasis by regulating hepatic glucose production (HGP). To examine this question, we utilized the H4IIE cell as a model of HGP. Inhibition of HGP in H4IIE cells from lactate and pyruvate was highly sensitive to physiological concentrations of insulin and metformin. Silencing of TCF7L2 protein expression induced a 5-fold increase in basal HGP (P<0.0001), and this was accompanied by marked increase in the expression of several key gluconeogenic genes. FBPase, PEPCK and G6Pase mRNA were up-regulated 2.5-fold (P<0.0001), 1.4-fold (P<0.01) and 2.3-fold (P<0.0001), respectively, compared to scramble siRNA. Compared to their respective baseline values, insulin and metformin suppressed HGP equally in the scramble and TCF7L2 siRNA cells, but HGP remained elevated in TCF7L2 silenced cells due to the increased baseline HGP. Using chromatin immunoprecipitation sequencing (ChIP-Seq), we investigated the direct transcriptional targets of TCF7L2 in hepatocytes. A total of 2119 ChIP peaks were detected, of which 36% were located inside gene boundaries and, overall, a total of 65% of all binding events were within 50 Kb of a gene. De novo motif analysis revealed remarkable conservation of the long and short TCF7L2 consensus binding sites in the rat hepatocytes. Pathway analysis showed that the top two disease categories over-represented in our dataset were “non-insulin dependent diabetes” (155 genes; P = 1.63 x 10-10) and “diabetes mellitus” (245 genes; P = 7.4 x 10-12). Inspection of genes in these categories revealed that TCF7L2 directly binds to multiple genes important in the regulation of glucose metabolism in the liver, including PEPCK, FBP1, IRS1, IRS2, AKT2 ADIPOR1, PDK4 and CPT1A. Our findings suggest a novel mechanism for the regulation of HGP by TCF7L2, and provide a possible explanation for the association of TCF7L2 polymorphisms with the incidence of T2DM. two samples: TCF7L2 ChIP-Seq and Input DNA
2011-09-12 | E-GEOD-28782 | biostudies-arrayexpress
Project description:The liver acts as a master regulator of metabolic homeostasis in part by performing gluconeogenesis. This process is dysregulated in type 2 diabetes, leading to elevated hepatic glucose output. The parenchymal cells of the liver (hepatocytes) are heterogeneous, existing on an axis between the portal triad and the central vein, and perform distinct functions depending on location in the lobule. Here, using single cell analysis of hepatocytes across the liver lobule, we demonstrate that gluconeogenic gene expression (Pck1 and G6pc) is relatively low in the fed state and gradually increases first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases, and following entry into the starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression to the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting state but only 1.5-fold higher in the starvation state. In parallel, starvation suppresses canonical beta-catenin signaling and modulates expression of pericentral and periportal glutamine synthetase and glutaminase, resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These findings demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule, underscoring the critical importance of using well-defined feeding and fasting conditions to define the basis of hepatic insulin resistance and glucose production.
2024-11-14 | PXD051593 | Pride
Project description:TCF7L2 is one of the strongest type 2 diabetes (T2DM) candidate genes to emerge from GWAS studies, but the mechanisms by which it regulates the pathways which are important in the pathogenesis of type 2 diabetes are unknown. Previous in vitro and in vivo studies have focused on the link between TCF7L2 and insulin secretion as an explanation for the association between TCF7L2 and T2DM. However, TCF7L2 and the Wnt/β-catenin pathway are important for metabolic zonation in the liver. This raises the interesting possibility that TCF7L2 may influence glucose homeostasis by regulating hepatic glucose production (HGP). To examine this question, we utilized the H4IIE cell as a model of HGP. Inhibition of HGP in H4IIE cells from lactate and pyruvate was highly sensitive to physiological concentrations of insulin and metformin. Silencing of TCF7L2 protein expression induced a 5-fold increase in basal HGP (P<0.0001), and this was accompanied by marked increase in the expression of several key gluconeogenic genes. FBPase, PEPCK and G6Pase mRNA were up-regulated 2.5-fold (P<0.0001), 1.4-fold (P<0.01) and 2.3-fold (P<0.0001), respectively, compared to scramble siRNA. Compared to their respective baseline values, insulin and metformin suppressed HGP equally in the scramble and TCF7L2 siRNA cells, but HGP remained elevated in TCF7L2 silenced cells due to the increased baseline HGP. Using chromatin immunoprecipitation sequencing (ChIP-Seq), we investigated the direct transcriptional targets of TCF7L2 in hepatocytes. A total of 2119 ChIP peaks were detected, of which 36% were located inside gene boundaries and, overall, a total of 65% of all binding events were within 50 Kb of a gene. De novo motif analysis revealed remarkable conservation of the long and short TCF7L2 consensus binding sites in the rat hepatocytes. Pathway analysis showed that the top two disease categories over-represented in our dataset were “non-insulin dependent diabetes” (155 genes; P = 1.63 x 10-10) and “diabetes mellitus” (245 genes; P = 7.4 x 10-12). Inspection of genes in these categories revealed that TCF7L2 directly binds to multiple genes important in the regulation of glucose metabolism in the liver, including PEPCK, FBP1, IRS1, IRS2, AKT2 ADIPOR1, PDK4 and CPT1A. Our findings suggest a novel mechanism for the regulation of HGP by TCF7L2, and provide a possible explanation for the association of TCF7L2 polymorphisms with the incidence of T2DM.
2011-09-12 | GSE28782 | GEO
Project description:Identification of binding protein of TCF7L2-L by LC/MS
2025-01-13 | PXD048102 | Pride
Project description: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., β-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.
2020-07-29 | GSE138781 | GEO
Project description:Analysis of the complex expression of claudin genes and transcription factors during intestinal epithelial cell differentiation across the crypt-to-surface colonic axis. Characterization of the complex expression gradients of transcription factors Hopx, Hnf4a, Klf4 and Tcfl2 and 12 claudin genes. In vitro confirmatory methods identified two pathways that stimulate claudin expression; Hopx/Klf4 activation of Cldn4, 7 and 15, and Tcf7l2/Hnf4a upregulation of Cldn23. Chromatin Immunoprecipitation confirmed a Tcf7l2/Hnf4a/Claudin23 cascade. Hnf4a conditional knockout mice fail to induce Cldn23 during colonocyte differentiation.
2016-07-23 | GSE84742 | GEO