Genome-wide occupancy of Tcf7l2/Tcf4 in rat and expression profiling of Tcf7l2 mutant and control mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA273063 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1767401.fastq.gz | Fastqsanger.gz | |||
| SRR1767402.fastq.gz | Fastqsanger.gz | |||
| SRR1767403.fastq.gz | Fastqsanger.gz | |||
| SRR1767404.fastq.gz | Fastqsanger.gz | |||
| SRR1767405.fastq.gz | Fastqsanger.gz |
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Project description:As part of our comprehensive characterization of intestinal development, we performed ChIP-seq for TCF7L2/TCF4 in mouse E16.5 intestinal epithelial cells. We identified more than 6000 regions bound by TCF7L2/TCF4 including a binding site in an enhancer driving Shh expression. Combined with transcriptional and functional analyses, our data reveal a novel cross-talk between WNT and Hedgehog signaling pathways.
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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:We performed genome-wide profiling of Tcf7l2 occupancy during oligodendrocyte differentiation and identified the key enzymes involved in cholesterol metabolism and essential for CNS myelination.
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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.
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Project description:TCF7L2 regulates multiple metabolic pathways in hepatocytes through a transcriptional network involving HNF4M-NM-1 For the identification of Tcf7l2 target genes using a RNA-seq timecourse, and for identifying the binding sites of Tcf7l2 and Hnf4a, Tcf7l2 was silenced in rat H4IIE hepatocytes using siRNA for Tcf7l2 with a scrambled siRNA as control. Treatment times for RNA-seq samples were 3, 6, 9, 12, 15, 18, 48, and 96 hours, and for ChIP-seq samples 15 h. RNA-seq timecourse was performed in duplicate or triplicate, and the ChIP-seq in duplicate for Tcf7l2 and in singlicate for Hnf4a. The H4IIE-specific transcriptome was defined from an independent set of pooled 24 h siRNA treated samples (N=3 for siRNA for Tcf7l2 and N=3 for scrambled siRNA).
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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
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Project description:This SuperSeries is composed of the SubSeries listed below.
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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:ChIP-seq for TCF7L2/TCF4 in E16.5 intestinal epithelial cells
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