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ChIP-seq for TCF7L2/TCF4 in E16.5 intestinal epithelial cells

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE164442 | GEO | 2021/12/11

REPOSITORIES: GEO

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ChIP-seq for TCF7L2/TCF4 in E16.5 intestinal epithelial cells

Project description:ChIP-seq for TCF7L2/TCF4 in E16.5 intestinal epithelial cells

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Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand

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 Î²-cells. Here, a mouse genetics approach shows that removal of TCF4 from Î²-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

Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand

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

Genome-wide occupancy of Tcf7l2/Tcf4 in rat and expression profiling of Tcf7l2 mutant and control mice

Project description:Genome-wide occupancy of Tcf7l2/Tcf4 in rat and expression profiling of Tcf7l2 mutant and control mice

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TCF4 germline mutation and adult-onset SHH medulloblastoma

Project description:Medulloblastoma (MB) is the most prevalent pediatric cerebral cancer, but is rare in adults. The vast majority of MB arises sporadically but some few cases occur in association with germline alterations in genes such as PTCH1, SUFU, APC, and TP53. Additional genes are responsible for MB predisposition including some that have probably not been described so far either due to the rarity of the cases and/or to the low penetrance. Here we report the case of a 27 years old woman affected by Pitt Hopkins syndrome due to a heterozygous germline pathogenic variant in TCF4 who has developed a Sonic Hedgehog (SHH)-driven MB. Somatic loss of function variants of TCF4 have been identified in SHH MB especially among adults and this case raises the question of a predisposition to late-onset SHH MB associated with TCF4 germline alteration.

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Genome-wide maps of Wnt effector Tcf7l2/Tcf4 occupancy in oligodendrocyte during CNS myelination

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TCF4 germline mutation and adult-onset SHH medulloblastoma

Project description:TCF4 germline mutation and adult-onset SHH medulloblastoma

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Genome-wide maps of Wnt effector Tcf7l2/Tcf4 occupancy in oligodendrocyte during CNS myelination

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Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells

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

TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions

Project description:Surprisingly few pathways signal between cells, raising questions about mechanisms for tissue-specific responses. In particular, Wnt ligands signal in many mammalian tissues, including the intestinal epithelium, where constitutive signaling causes cancer. Genome-wide analysis of DNA cis-regulatory regions bound by the intestine-restricted transcription factor CDX2 in colonic cells uncovered highly significant over-representation of sequences that bind TCF4, a transcriptional effector of intestinal Wnt signaling. Chromatin immunoprecipitation confirmed TCF4 occupancy at most such sites and co-occupancy of CDX2 and TCF4 across short distances. A region spanning the single nucleotide polymorphism rs6983267, which lies within a MYC enhancer and confers colorectal cancer risk in humans, represented one of many co-occupied sites. Co-occupancy correlated with intestine-specific gene expression and CDX2 loss reduced TCF4 binding.These results implicate CDX2 in directing TCF4 binding in intestinal cells. Co-occupancy of regulatory regions by signal-effector and tissue-restricted transcription factors may represent a general mechanism for ubiquitous signaling pathways to achieve tissue-specific outcomes. A series of ChIP-chip experiments identified the CDX2 cistrome and discovered and validated extensive co-binding with TCF4 in colon cancer cell lines Transcriptional profiling following shRNA-mediated CDX2 knockdown was employed to identify CDX2-dependent gene expression in the human colon cancer cell line Caco2

2010-08-11 | E-GEOD-22572 | biostudies-arrayexpress

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