β-catenin/Tcf7l2 dependent transcriptional regulation of GLUT1 gene expression by Zic family proteins in colon cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA525873 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24489376.fastq.gz | Fastqsanger.gz | |||
| SRR24489377.fastq.gz | Fastqsanger.gz | |||
| SRR24489378.fastq.gz | Fastqsanger.gz | |||
| SRR24489379.fastq.gz | Fastqsanger.gz | |||
| SRR24489380.fastq.gz | Fastqsanger.gz |
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Project description:The Zinc finger of the cerebellum (ZIC) proteins have been implicated to function in normal tissue development. Mutations or deletions of ZIC genes have been found to be associated with neural-related abnormalities. Recent studies point out the critical functions of Zic proteins in cancers and the potential tumor suppressive functions in colon cancer development and progression. To elucidate the functional roles of Zic proteins in colorectal cancer, we employed CRISPR/Cas9 genome editing to knock out the Zic5 gene and analyze the chromatin localization pattern and transcriptional regulation of target gene expression. Zic5 regulates glucose metabolism through the regulation of expression of the GLUT1/SLC2A1 gene. Zic5 knockout is accompanied by an increased glycolytic state, tolerance to a low glucose condition, and derepression of metabolic genes especially GLUT1 gene expression. Reciprocally, the loss of Zic2 partially restored the glucose uptake by decreasing GLUT1 gene expression, pointing out the balance between the different Zic family proteins. Mechanistically, Zic5 is recruited by the β-catenin/TCF7l2 complex to the promoters of the target genes. Loss of β-catenin or TCF7l2 significantly diminishes the chromatin binding of Zic5 globally. Our studies suggest that the Wnt/β-catenin signaling pathway has a strong influence on the function of Zic proteins and glucose metabolism in colorectal cancers through GLUT1, thus interfering Wnt/β-catenin - Zic5 axis regulated aerobic glycolysis represents a potentially effective strategy to selectively target colon cancer cells.
2019-08-20 | GSE127960 | GEO
Project description:The zinc finger of the cerebellum (ZIC) proteins has been implicated to function in normal tissue development. Recent studies have described the critical functions of Zic proteins in cancers and the potential tumor-suppressive functions in colon cancer development and progression. To elucidate the functional roles of Zic proteins in colorectal cancer, we knocked out the Zic5 gene and analyzed the chromatin localization pattern and transcriptional regulation of target gene expression. We found that Zic5 regulates glucose metabolism, and Zic5 knockout is accompanied by an increased glycolytic state and tolerance to a low-glucose condition. Furthermore, loss of β-catenin or TCF7l2 diminishes the chromatin binding of Zic5 globally. Our studies suggest that the Wnt/β-catenin signaling pathway has a strong influence on the function of Zic proteins and glucose metabolism in colorectal cancers through GLUT1. Interfering Wnt/-catenin-Zic5 axis-regulated aerobic glycolysis represents a potentially effective strategy to selectively target colon cancer cells.
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Project description:Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi- persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells; confirming the mechanistic role of the β-catenin-TCF7L2- JMJD6-MYC axis in BETi-resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared to sensitive sAML blasts, displayed higher mRNA and protein expressions of TCF7L2, JMJD6 and c-Myc, and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of co-localization of nuclear β-catenin with TBL1 and TCF7L2 by the small molecule inhibitor BC2059 combined with depletion of BRD4 by BET-PROTAC reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or with patient-derived AML blasts innately resistant to BETi. Therefore, multi- targeted disruption of β-catenin-TCF7L2-JMJD6-MYC axis overcomes adaptive and innate BETi-resistance, exhibiting pre-clinical efficacy against human post-MPN sAML cells.
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Project description:Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi- persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells; confirming the mechanistic role of the β-catenin-TCF7L2- JMJD6-MYC axis in BETi-resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared to sensitive sAML blasts, displayed higher mRNA and protein expressions of TCF7L2, JMJD6 and c-Myc, and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of co-localization of nuclear β-catenin with TBL1 and TCF7L2 by the small molecule inhibitor BC2059 combined with depletion of BRD4 by BET-PROTAC reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or with patient-derived AML blasts innately resistant to BETi. Therefore, multi- targeted disruption of β-catenin-TCF7L2-JMJD6-MYC axis overcomes adaptive and innate BETi-resistance, exhibiting pre-clinical efficacy against human post-MPN sAML cells.
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Project description:Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi- persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells; confirming the mechanistic role of the β-catenin-TCF7L2- JMJD6-MYC axis in BETi-resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared to sensitive sAML blasts, displayed higher mRNA and protein expressions of TCF7L2, JMJD6 and c-Myc, and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of co-localization of nuclear β-catenin with TBL1 and TCF7L2 by the small molecule inhibitor BC2059 combined with depletion of BRD4 by BET-PROTAC reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or with patient-derived AML blasts innately resistant to BETi. Therefore, multi- targeted disruption of β-catenin-TCF7L2-JMJD6-MYC axis overcomes adaptive and innate BETi-resistance, exhibiting pre-clinical efficacy against human post-MPN sAML cells.
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Project description:Activation of the evolutionarily conserved, developmental Wnt pathway has been reported during maladaptive cardiac remodeling. Although the function of Wnt-transcriptional activation in development is well described, the consequences of Wnt pathway activation, as well as its cardiac-specific regulatory role in the adult heart, is largely unknown. We show that β-catenin and Transcription factor 7-like 2 (TCF7L2), the main nuclear components of the Wnt-transcriptional cascade, and their transcriptional activity are increased upon pathological remodeling in both murine and human hearts. To understand the consequences of increased Wnt signaling pathway activity, we utilized an in vivo mouse model in which β-catenin is acutely stabilized in adult cardiomyocytes (CM), leading to increased ventricular TCF7L2 expression and activation of its target genes. Mice with stabilized β-catenin displayed cardiac hypertrophy, increased mortality, reduced cardiac function and altered calcium homeostasis, similar to experimentally induced hypertrophy. Moreover, we observed a re-activation of Wnt-dependent developmental gene programs including activation of the Wnt/β-catenin-independent pathway, increased CM cell cycling with poly-nucleation and cytoskeletal disorganization, underscoring a central role in adult tissue remodeling. By integrating transcriptome analyses and genome-wide occupancy (ChIP-seq) of the endogenous ventricular TCF7L2, we show that upon aberrant Wnt activation, TCF7L2 induces context and Wnt-specific gene regulation in pathological remodeling. Interestingly, β-catenin stabilized ventricles showed increased histone H3 lysine 27 acetylation (H3K27ac) and TCF7L2 recruitment to novel disease-associated gene-specific enhancers. Importantly, using integrative motif analyses and experimental evidences, our data uncovered a role for GATA4 as a cardiogenic regulator of TCF7L2/β-catenin complex and established a paradigm for cell-specific effects of Wnt signaling. Altogether, our studies unraveled the nuclear Wnt-TCF7L2-associated chromatin landscape and its role in adult tissue remodeling leading to heart failure.
2018-01-23 | GSE97761 | GEO
Project description:Summary: Activation of the evolutionarily conserved, developmental Wnt pathway has been reported during maladaptive cardiac remodeling. Although the function of Wnt-transcriptional activation in development is well described, the consequences of Wnt pathway activation, as well as its cardiac-specific regulatory role in the adult heart, is largely unknown. We show that β-catenin and Transcription factor 7-like 2 (TCF7L2), the main nuclear components of the Wnt-transcriptional cascade, and their transcriptional activity are increased upon pathological remodeling in both murine and human hearts. To understand the consequences of increased Wnt signaling pathway activity, we utilized an in vivo mouse model in which β-catenin is acutely stabilized in adult cardiomyocytes (CM), leading to increased ventricular TCF7L2 expression and activation of its target genes. Mice with stabilized β-catenin displayed cardiac hypertrophy, increased mortality, reduced cardiac function and altered calcium homeostasis, similar to experimentally induced hypertrophy. Moreover, we observed a re-activation of Wnt-dependent developmental gene programs including activation of the Wnt/β-catenin-independent pathway, increased CM cell cycling with poly-nucleation and cytoskeletal disorganization, underscoring a central role in adult tissue remodeling. By integrating transcriptome analyses and genome-wide occupancy (ChIP-seq) of the endogenous ventricular TCF7L2, we show that upon aberrant Wnt activation, TCF7L2 induces context and Wnt-specific gene regulation in pathological remodeling. Interestingly, β-catenin stabilized ventricles showed increased histone H3 lysine 27 acetylation (H3K27ac) and TCF7L2 recruitment to novel disease-associated gene-specific enhancers. Importantly, using integrative motif analyses and experimental evidences, our data uncovered a role for GATA4 as a cardiogenic regulator of TCF7L2/β-catenin complex and established a paradigm for cell-specific effects of Wnt signaling. Altogether, our studies unraveled the nuclear Wnt-TCF7L2-associated chromatin landscape and its role in adult tissue remodeling leading to heart failure. Purpose: The aim of this study was to compare transcriptome profiles (RNA-seq) of normal (containing a Cre recombinase positive locus- Cre "positive" control with a WT β-catenin locus; to eliminate effects of Cre-mediated cardiac toxicity) and β-catenin stabilized murine adult cardiac ventricles. Methods: Adult cardiac tissue mRNA profiles for normal and Wnt-activated mice were obtained using deep sequencing, in triplicates, using Illumina HiSeq2000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat followed by DESeq2. qPCR validation was performed using TaqMan and SYBR Green assays Conclusions: Our study represents the first detailed analysis of the processes triggered upon Wnt activation in the adult heart, which was so far, not investigated. We report that this Wnt activation in the adult heart maintains its developmental function; however due to the lack of adequate developmental plasticity in the adult heart, culminates in pathological remodeling.
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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
2011-09-12 | E-GEOD-28782 | biostudies-arrayexpress
Project description:In mammals, Wnt pathway is activated during both heart regeneration post-injury and disease. Our previous work described the role of nuclear Wnt effectors B-catenin and Transcription factor 7-like 2 (TCF7L2) in heart disease progression; revealing GATA4 as a Wnt-repressor in the healthy adult heart. However, there is an urgent need to dissect molecular players distinguishing regenerative vs. disease-specific responses. In this study, we report a GATA4-B-catenin interaction in the regenerative neonatal myocardium, despite high TCF7L2 expression. TCF7L2 displayed strikingly unique genomic occupancies: proximal in neonatal and distal in diseased hearts. Integrative genomic and transcriptomic analyses showed that TCF7L2 differentially occupied and regulated fatty acid metabolic genes in the neonatal; and cardiac developmental and vasculogenesis genes in the diseased hearts, clearly discerning these two cardiac states. De-novo motif search identified TEAD as a commonly enriched motif in both TCF7L2 and GATA4-bound regions in the neonatal hearts, suggesting its potential role in providing a regenerative context to this GATA4-B-catenin interaction. Altogether, our study mapped for the first time, novel genome-wide TCF7L2 and GATA4 targets in the neonatal hearts and identified stage-specific roles for the cardiac Wnt-GATA4 complex. These findings demonstrate strong context-specificity of the cardiac Wnt-nuclear complex, which can be further exploited for therapeutic avenues.
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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