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Identification of beta-cetenin/TCF4 target genes in LS174T colorectal cancer cells using gene expression arrays

ABSTRACT: Aberrant activation of WNT signaling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 competes with beta-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been previously linked to increased susceptibility to develop CRC. Hence, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56896 | GEO | 2014/05/20

SECONDARY ACCESSION(S): PRJNA244875

REPOSITORIES: GEO

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Identification of beta-cetenin/TCF4 target genes in LS174T colorectal cancer cells using gene expression arrays

Project description:Aberrant activation of WNT signaling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 competes with beta-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been previously linked to increased susceptibility to develop CRC. Hence, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation. A 4-hydoxy tamoxifen inducible system was used to inducibly block beta-catenin/TCF activity for a period of 36h. Briefly, the ERT2 domain from the pCMV-CRE-ERT2 (Feil et al., 1996) was amplified by PCR and cloned into a modified FUGW lentiviral vector backbone (Lois et al., 2002). NTCF was then amplified byPCR from the pCDNA3.1-NTCF-NLS (van de Wetering et al., 2002) and cloned in frame upstream of the ERT2 from the FUW-CMV-ERT2 (ET) to create the FUW-CMV-NTCF-ERT2 (NET). Total RNA was extracted using the TRIzolM-BM-. Plus RNA Purification Kit (Life Technologies).

2014-05-20 | E-GEOD-56896 | biostudies-arrayexpress

Identification of GATA6 target genes in LS174T colorectal cancer cells using gene expression arrays

2014-05-20 | GSE56895 | GEO

Identification of GATA6 target genes in LS174T colorectal cancer cells using gene expression arrays

Project description:Aberrant activation of WNT signaling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 competes with beta-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been previously linked to increased susceptibility to develop CRC. Hence, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation. Total RNA was collected from biological replicates of LS174T colorectal cancer cells transduced with either short hairpin against GATA6 (shGATA6) or non-silencing control (NS) grown in DMEM supplemented with 10% FBS in the presence of doxycycline (dox: 1 Âµg mL-1; Sigma Aldrich) or vehicle (70% ethanol) for a period of 72h. Short hairpins were designed and cloned into doxycycline inducible pTRIPZ lentiviral vector (Open Biosystems). Additionally a 4-hydoxy tamoxifen inducible system was used to inducibly block beta-catenin/TCF activity for a period of 36h. Briefly, the ERT2 domain from the pCMV-CRE-ERT2 (Feil et al., 1996) was amplified by PCR and cloned into a modified FUGW lentiviral vector backbone (Lois et al., 2002). NTCF was then amplified byPCR from the pCDNA3.1-NTCF-NLS (van de Wetering et al., 2002) and cloned in frame upstream of the ERT2 from the FUW-CMV-ERT2 (ET) to create the FUW-CMV-NTCF-ERT2 (NET). Total RNA was extracted using the TRIzolÂ® Plus RNA Purification Kit (Life Technologies).

2014-05-20 | E-GEOD-56895 | biostudies-arrayexpress

The transcription factor GATA6 allows self-renewal of colon adenoma stem cells by repressing BMP gene expression.

2014-06-19 | E-GEOD-49479 | biostudies-arrayexpress

The transcription factor GATA6 allows self-renewal of colon adenoma stem cells by repressing BMP gene expression.

2014-06-19 | GSE49479 | GEO

Genome-wide map of GATA6 DNA binding in human CRC cells

Project description:We describe the genome-wide DNA-binding of GATA6 in a human CRC cell line (LS174T). GATA6 is found to bind the promoter of genes involved in the maintenance of intestinal stem cells, including genes of the Wnt and TGFbeta/BMP pathways. With this we describe a novel GATA6-dependent mechanism of stem cell maintenance in colorectal tumors. Examination of GATA6 binding and H3K4me1, H3K4me3 and H3K27ac levels in a human CRC cell line by Chromatin immunoprecipitation followed by deep sequencing.

2014-05-20 | E-GEOD-49320 | biostudies-arrayexpress

Genome-wide map of GATA6 DNA binding in human CRC cells

2014-05-20 | GSE49320 | GEO

Gene expression profiles of DLD1 cells in which GATA6 or LGR5 expression was suppressed.

Project description:Mutations in APC or β-catenin that cause aberrant activation of Wnt signaling are responsible for the initiation of colorectal tumor development. LGR5 is specifically expressed in stem cells of the intestine, stomach and hair follicle, and plays essential roles in maintaining tissue homeostasis. LGR5-positive stem cells have been shown to be responsible for the intestinal adenoma initiated by some mutations in APC . Furthermore, it has recently been reported that Lgr5, which is associated with the Frizzled/Lrp Wnt receptor complex, interacts with R-spondins and thereby activates Wnt signaling. However, the function of LGR5 in colorectal tumorigenesis has been unclear. Here we show that LGR5 is required for the tumorigenicity of colorectal cancer cells. We also show that the transcription factor GATA6 directly enhances the expression of LGR5. DLD1 cells were infected with a lentivirus expressing an shRNA targeting GATA6 or LGR5.

2011-10-17 | E-GEOD-32987 | biostudies-arrayexpress

The effect of CHRDL2 overexpression on gene expression in CACO2 CRC cells

Project description:Chordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression and genomic variants associated with colorectal cancer (CRC) risk. BMP signalling in the normal intestinal epithelium operates in opposition to the WNT signalling pathway, which maintains stem-cells and self-renewal. Elevated WNT signalling leads to expansion of the stem cell compartment and hyperproliferation, defining characteristics of CRC. Here, we explored the impact of CHRDL2 overexpression on CRC cells to investigate whether CHRDL2's inhibition of BMP signalling intensified WNT signalling, and enhanced the cancer stem-cell phenotype. RNA-seq analysis revealed that CHRDL2 increased the expression of stem cell markers and well-established cancer-associated pathways. We suggest that CHRDL2 overexpression can augment the stem-cell potential of CRC and normal intestinal cells.

2024-01-22 | GSE253554 | GEO

Transcription profiling ofmouse wild type and GATA6 null lung

Project description:Epithelial organs including the lung are known to possess regenerative abilities through activation of endogenous stem cell populations but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation in Gata6 null lung epithelium. This expansion of BASCs is the result of a dramatic increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the non-canonical Wnt receptor Fzd2 is down-regulated in Gata6 mutants and increased Fzd2 or decreased Î²-catenin expression rescues, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, we show that canonical Wnt signaling is activated in the niche containing BASCs and forced activation of Wnt signaling leads to a dramatic increase in BASC numbers. Moreover, Gata6 is required for proper lung epithelial regeneration and postnatal loss of Gata6 leads to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6 regulated Wnt signaling controls the balance between stem/progenitor expansion and epithelial differentiation required for both lung development and regeneration. Experiment Overall Design: 3 replicates of each condition-wild-type and GATA6 null tissue. 6 total samples.

2008-06-11 | E-GEOD-11165 | biostudies-arrayexpress

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