A b-catenin-TCF-sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer
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ABSTRACT:
PROVIDER: PRJNA721386 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14213500.fastq.gz | Fastqsanger.gz | |||
| SRR14213501.fastq.gz | Fastqsanger.gz | |||
| SRR14213502.fastq.gz | Fastqsanger.gz | |||
| SRR14213503.fastq.gz | Fastqsanger.gz | |||
| SRR14213504.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims. Sporadic colorectal cancers arise from mutations in APC, producing oncogenic β-catenin/TCF-dependent transcriptional reprogramming. The tumor suppressor axis regulated by the intestinal epithelial receptor, GUCY2C, is among the earliest pathways silenced in tumorigenesis. Retention of the receptor, but loss of its paracrine ligands, guanylin and uroguanylin, is an evolutionarily conserved feature of colorectal tumors, arising in the earliest dysplastic lesions. Here, we examined a mechanism of GUCY2C ligand transcriptional silencing by β-catenin/TCF signaling. Methods. We performed RNA-seq analysis of four unique conditional human colon cancer cell models of β-catenin/TCF signaling to map the core Wnt-transcriptional program. We then performed a comparative analysis of orthogonal approaches, including luciferase reporters, ChIP-seq, CRISPR Cas9 knockout, and CRISPR epigenome editing, which were cross-validated with human tissue ChIP-seq datasets, to identify functional gene enhancers mediating GUCY2C ligand loss. Results. RNA-seq analyses reveal the GUCY2C hormones as two of the most sensitive targets of β-catenin/TCF signaling, reflecting transcriptional repression. The GUCY2C hormones share an insulated genomic locus containing a novel locus control region upstream of the guanylin promoter that mediates the coordinated silencing of both genes. Targeting this region with CRISPR epigenome editing reconstituted GUCY2C ligand expression, overcoming gene inactivation by mutant β-catenin/TCF signaling. Conclusions. These studies reveal novel DNA elements regulating co-repression of GUCY2C ligand transcription by β-catenin/TCF signaling, reflecting a novel pathophysiological step in tumorigenesis. They offer unique genomic strategies that could re-establish hormone expression in the context of canonical oncogenic mutations to reconstitute the GUYC2C axis and oppose transformation.
2022-01-03 | GSE171910 | GEO
Project description:Background & aimsSporadic colorectal cancers arise from initiating mutations in APC, producing oncogenic β-catenin/TCF-dependent transcriptional reprogramming. Similarly, the tumor suppressor axis regulated by the intestinal epithelial receptor GUCY2C is among the earliest pathways silenced in tumorigenesis. Retention of the receptor, but loss of its paracrine ligands, guanylin and uroguanylin, is an evolutionarily conserved feature of colorectal tumors, arising in the earliest dysplastic lesions. Here, we examined a mechanism of GUCY2C ligand transcriptional silencing by β-catenin/TCF signaling.MethodsWe performed RNA sequencing analysis of 4 unique conditional human colon cancer cell models of β-catenin/TCF signaling to map the core Wnt-transcriptional program. We then performed a comparative analysis of orthogonal approaches, including luciferase reporters, chromatin immunoprecipitation sequencing, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) knockout, and CRISPR epigenome editing, which were cross-validated with human tissue chromatin immunoprecipitation sequencing datasets, to identify functional gene enhancers mediating GUCY2C ligand loss.ResultsRNA sequencing analyses reveal the GUCY2C hormones as 2 of the most sensitive targets of β-catenin/TCF signaling, reflecting transcriptional repression. The GUCY2C hormones share an insulated genomic locus containing a novel locus control region upstream of the guanylin promoter that mediates the coordinated silencing of both genes. Targeting this region with CRISPR epigenome editing reconstituted GUCY2C ligand expression, overcoming gene inactivation by mutant β-catenin/TCF signaling.ConclusionsThese studies reveal DNA elements regulating corepression of GUCY2C ligand transcription by β-catenin/TCF signaling, reflecting a novel pathophysiological step in tumorigenesis. They offer unique genomic strategies that could reestablish hormone expression in the context of canonical oncogenic mutations to reconstitute the GUCY2C axis and oppose transformation.
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Project description:During canonical Wnt signalling the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones simultaneously carrying loss-of-function alleles of all four TCF/LEF genes. Exploiting unbiased whole transcriptome sequencing studies, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors.
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Project description:During canonical Wnt signalling the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones simultaneously carrying loss-of-function alleles of all four TCF/LEF genes. Exploiting unbiased whole transcriptome sequencing studies, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors.
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Project description:Both TCF-1 and its coactivator β-catenin are known to be required for supporting normal double positive (DP) thymocyte survival through upregulating Bcl-xL. However, the downstream factors mediating this effect remained unknown. We used microarray to compare the global expression difference among WT, TCF-1-deficient, and β-catenin transgenic thymocytes to search for the genes that are down-regulated and up-regulated in TCF-1-deficient and β-catenin transgenic thymocytes, respectively. We focus on the genes that are significantly down-regulated and up-regulated in TCF-1-deficient and β-catenin transgenic thymocytes, respectively, to select for those genes that are potential target genes of β-catenin/TCF-1 pathway. And then those genes are subject to IPA pathway analysis searching for genes that are involved in thymocyte development and cell death.
2011-08-31 | E-GEOD-31371 | biostudies-arrayexpress
Project description:Both TCF-1 and its coactivator β-catenin are known to be required for supporting normal double positive (DP) thymocyte survival through upregulating Bcl-xL. However, the downstream factors mediating this effect remained unknown. We used microarray to compare the global expression difference among WT, TCF-1-deficient, and β-catenin transgenic thymocytes to search for the genes that are down-regulated and up-regulated in TCF-1-deficient and β-catenin transgenic thymocytes, respectively.
2011-09-01 | GSE31371 | GEO
Project description:We report ChIP-Seq experiments to profile the genomic binding dynamics of ß-catenin, SOX17, SOX2 and TCF/LEF TFs in definitive endoderm and neuromesodermal progenitor cells and RNA-Seq/ATAC-Seq experiments for transcriptomic and chromatin profiling of these cell types.
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Project description:Constitutive activation of Wnt/β-catenin signaling drives tumor initiation, maintenance, and metastasis in numerous preclinical models. Within the nucleus, β-catenin interacts with transcription factors of the TCF/LEF (T cell factor/lymphoid enhancer factor, TCFs) family. The transcriptional program mediated by these β-catenin/TCF interactions promotes cell proliferation, epithelial-mesenchymal transition (EMT), and a cancer stem-cell phenotype. COLO320DM is a human colorectal cancer line with an activated Wnt/ β-catenin pathway driven by an APC mutation. Here, we apply a doxycycline-inducible shRNA to knockdown (KD) CTNNB1 (encoding β-catenin) and study the impact on the global transcriptome of COLO320DM. We also design and express an shRNA-resistant rescue cDNA to rule out any potential off-target effect. The results reveal a global gene expression change upon CTNNB1-KD that is consistent with β-catenin’s role in serving as a signal hub downstream of the canonical Wnt pathway.
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2013-11-01 | E-GEOD-42512 | biostudies-arrayexpress
Project description:The Wnt signaling pathway is involved in many differentiation events during embryonic development and can lead to tumor formation after aberrant activation of its components. ?-catenin, a cytoplasmic component, plays a major role in the transduction of the canonical wnt/ ?-catenin signaling. The aim of this study was to identify novel genes that are regulated by active ?-catenin/TCF signaling in hepatocellular carcinoma. We selected and expanded isogenic clones from hepatocellular carcinoma-derived Huh7 cells with high and low ?-catenin/TCF activities. We showed that, high TCF activity Huh7 cells lead to bigger and more aggressive tumors when xenografted into nude mice. We used SAGE (Serial Analysis of Gene Expression), genome-wide microarray and in silico promoter analysis in parallel, to compare gene expression between low (basal) and high (transfected) ?-catenin/TCF activity clones, those had been xenografted into nude mice. We compared and contrasted SAGE and genome-wide microarray data, in parallel. Finally; after combined analysis, we identified BRI3 and HSF2 as novel targets of Wnt/?-catenin signaling in hepatocellular carcinoma. High TCF activity Huh7 cell line (Huh7-S33Y) was compared to control Huh7 cell line (Huh7-Vec) by using 25 ug of total RNA isolated from each sample
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