ChIP-Seq for TCF7L2 in adult mouse thalami
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Covaris S220, Illumina NovaSeq 6000
ORGANISM(S): Mus musculus
SUBMITTER: Michał Szeląg
PROVIDER: E-MTAB-9384 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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).
2014-11-24 | E-GEOD-53862 | biostudies-arrayexpress
Project description:The thalamus of the brain acts as a relay station; taking inputs from several parts of the brain and then sending the information to the cortex and vice versa. It is also the structure know to affected in several brain developmental disorders such as schizophrenia, autism spectrum disorders, bipolar disorders etc. Upon in situ hybridisation one can visualise the expression of the transcription factor Tcf7l2 to be highest in prosomeric regions of the thalamus throughout development. With this information in mind we set out to find out, if the expression of Tcf7l2 is essential for the identity of the thalamic structure. Therefore, Tcf7l2 was knocked (KO) out using Cre+mice at embryonic stage E18.5 and postnatal adult stage P60. The E18.5 Tcf7l2 KO is a total knockout and the P60 Tcf7l2 KO is neuron-specific knockout. Total RNA was extracted and sent for sequencing using Illumina 2500. The data obtained was aligned by HISAT2 alignment tool, and the excon read counts were gathered using htseq counts, and expression normalization and differential gene expression was analysed using DESeq2.
2020-02-10 | E-MTAB-8755 | biostudies-arrayexpress
Project description:Identification of binding protein of TCF7L2-L by LC/MS
2025-01-13 | PXD048102 | Pride
Project description:Identification of TCF7L2 RNA binding proteins by LC/MS
2025-01-13 | PXD048312 | Pride
Project description:The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in 6 human cell lines. We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the 6 cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3. Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation. RNAseq analysis of MCF7 cells transfected with siCONTROL, siTCF7L2 or siGATA3. ChIP-seq analysis of H3K27ac, H3K4me1, H3K27me3, H3K9me3 in MCF7 cells; H3K4me1 and H3K27ac in HCT116 cells.
2012-06-05 | E-GEOD-38447 | biostudies-arrayexpress
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: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:CUT&RUN was performed for Sox2 on ex-vivo dissected visual thalamic nuclei from P0 mice, revealing context specific activity of Sox2 binding in differentiated neurons.
2023-06-03 | E-MTAB-13004 | biostudies-arrayexpress
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:The transcription factor TCF7L2 is indispensable for intestinal tissue homeostasis where it transmits mitogenic Wnt/β-Catenin signals in stem and progenitor cells, from which intestinal tumors arise. Yet, TCF7L2 belongs to the most frequently mutated genes in colorectal cancer (CRC), and growth inhibitory functions of TCF7L2 were proposed. This apparent paradox calls for a clarification of the role of TCF7L2 in colorectal carcinogenesis. Here, we investigated TCF7L2 dependence/independence of CRC cells, and the cellular and molecular consequences of TCF7L2 loss-of-function. By genome editing we readily achieved complete TCF7L2 inactivation in several CRC cell lines without loss of viability, showing that CRC cells have widely lost the strict requirement for TCF7L2. Albeit phenotypic changes manifested in a cell-line-specific fashion, TCF7L2-negative cells exhibited morphological changes, enhanced migration and invasion, and augmented collagen adhesion. Additionally, TCF7L2 deficiency led to reduced proliferation, reminiscent of the physiological role of TCF7L2. To provide a molecular framework for the observed phenotypic changes, we performed global transcriptome profiling. This identified gene-regulatory networks in which TCF7L2 positively regulates the proto-oncogene MYC, while repressing the cell cycle inhibitors CDKN2C/CDKN2D. TCF7L2 also suppresses the pro-metastatic transcription factor RUNX2 and several integrin genes, which is consistent with increased motility and collagen adhesion of TCF7L2-deficient cells. Altogether, we conclude that the proliferation-stimulating activity of TCF7L2 persists in CRC cells. Additionally, TCF7L2 acts as invasion suppressor. Despite its negative impact on cell cycle progression, TCF7L2 loss-of-function may thereby increase malignancy, which could explain why TCF7L2 is mutated in a sizeable fraction of colorectal tumors.
2020-03-20 | GSE135328 | GEO