Brg1 plays an essential role for intestinal tumor stem cells to maintain intestinal tumors in mice and human colorectal cancer cells
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ABSTRACT:
PROVIDER: PRJNA717242 | ENA |
REPOSITORIES: ENA
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Project description:Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for intestinal stem cells in mice. Therefore, we investigated the role of BRG1 in human colorectal cancer cells. We found that BRG1 was essential for maintainance of stem cell properties of human colorectal cancer cells.
2022-03-31 | GSE169627 | GEO
Project description:Brg1 has been reported to act as a trans-activator for the Wnt pathway by interacting with beta-catenin. Given this interaction and the crucial role Wnt signalling plays in the intestinal homeostasis, we aimed to investigate the effect of Brg1 loss on gene expression in normal and Wnt activated small intestinal epithelium. We used VillinCreERT2 Cre recombinase and loxP targeted allels of Brg1 and Apc to generate 4 cohorts of conditional knock-out mice: Cre-negative controls (n=4), Brg1 deficient (n=4), Apc deficient (n=3) and double Brg1-Apc deficient (n=4). All mice were induced by 4x80mg/kg daily injections of Tamoxifen. Epithelium enriched (gut scrapes) samples of small intestine (jejunum) were collected at day 4 post induction. Loss of Brg1 expression in the small intestinal epithelium at this time point was confirmed by immunohistochemistry.
2013-08-07 | E-GEOD-46129 | biostudies-arrayexpress
Project description:Brg1 has been reported to act as a trans-activator for the Wnt pathway by interacting with beta-catenin. Given this interaction and the crucial role Wnt signalling plays in the intestinal homeostasis, we aimed to investigate the effect of Brg1 loss on gene expression in normal and Wnt activated small intestinal epithelium.
2013-08-07 | GSE46129 | GEO
Project description:The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the ATPase subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression, however aberrant remodeling and gene expression can result in cancer. The function and localization on chromatin of the SWI/SNF complex depends on the protein makeup of the complex. Here we report the protein-protein interactions of wild-type BRG1 or mutant BRG1 in which the HSA domain has been deleted (BRG1-HSA). We demonstrate the interaction of BRG1 with most SWI/SNF complex members and a failure of a number of these members to interact with BRG1-HSA. These results demonstrate that the HSA domain of BRG1 is a critical interaction platform for the correct formation of SWI/SNF remodeling complexes.
2023-02-15 | PXD029647 | Pride
Project description:To determine the molecular regulation of ILC3s by Brg1, small intestinal ILC3s (Lin-Thy1highCD45low) from Brg1-deficient and control ILC3s were subjected to assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq).
2020-07-01 | GSE148078 | GEO
Project description:Long non-coding RNAs (lncRNAs) are regulatory RNAs, which by altering gene expression impact on the cellular phenotype and cardiovascular disease development. The pool of endothelial lncRNAs and their vascular function is largely undefined. Deep-endothelial RNA-Seq and FANTOM5 CAGE analysis revealed LINC00607 as a specifically enriched and highly expressed lncRNA in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA Knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout HUVEC also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored the normal function. RNA- and ATAC-Seq of the LINC00607 knockout revealed changes in transcription of endothelial gene sets particularly linked to the endothelial phenotype. This was most likely the consequence of a reduced chromatin accessibility of the ERG binding motif. Mechanistically, LINC00607 interacts with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is a highly expressed endothelial-specific lncRNA important for efficient endothelial gene transcription through sustaining ERG target gene transcription by interaction with the chromatin remodeler BRG1.
2023-01-09 | GSE201824 | GEO
Project description:Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor that is refractory to existing therapeutic regimens due in part to the presence of stem-like cells, termed Glioma-Initiating Cells (GICs). The complex interactions between different signaling pathways and epigenetic regulation of key genes may be critical in the maintaining GICs in their stem-like state. Although several signaling pathways have been identified as being dysregulated in GBM, the prognosis of GBM patients remains miserable despite improvements in targeted therapies. In this report we identified that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex plays a fundamental role in the maintaining GICs in their stem-like state. In addition, we identified a novel mechanism by which BRG1 maintains glucose levels critical for GICs. BRG1 downregulates the expression of TXNIP, a negative regulator of glycolysis. BRG1 knockdown led to STAT3 upregulation, which in turn led to TXNIP activation. We further identified that TXNIP is a STAT3-regulated gene. Moreover, BRG1 suppressed the expression of interferon-stimulated genes, which regulate tumorigenesis. We also demonstrate that BRG1 plays a critical role in the drug resistance of GICs and in GIC-induced tumorigenesis. By genetic and pharmacological means, we found that inhibition of BRG1 can sensitize GICs to chemotherapeutic drugs, temozolomide and Carmustine. Our studies suggest that BRG1 may be a novel therapeutic target in GBM. The identification of the critical role that BRG1 plays GIC stemness and chemosensitivity in GICs will inform the development of better targeted therapies in GBM and possibly other cancers.
2018-07-03 | GSE116545 | GEO
Project description:We found binding of the remodeling protein BRG1 was programmed by lineage and activation signals. BRG1 binding was positively correlated with gene activity at protein-coding and miRNA genes. BRG1 binding was found at promoters and distal regions, including known and novel distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites possessed enhancer activity, suggesting a general role for BRG1 in long-distance gene regulation. Together, these findings suggest BRG1 interprets differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings indicate BRG1 binding is a useful marker for identifying cis-regulatory regions in protein-coding and miRNA genes. Compare BRG1 binding in T helper subsets genome wide; Naïve, resting Th1, resting Th2, Stimulated Th1, Stimulated Th2, Stimulated Th17, compared to input DNA as negative control
2011-03-01 | E-GEOD-23719 | biostudies-arrayexpress
Project description:We report that Dnmt1 is crucial during perinatal intestinal development. Loss of Dnmt1 in intervillus progenitor cells causes global hypomethylation, DNA damage, premature differentiation, and apoptosis, and consequently, loss of nascent villi. We further confirm the critical role for Dnmt1 during crypt development using the in vitro organoid culture system, and illustrate a clear differential requirement for Dnmt1 in immature versus mature organoids. These results demonstrate an essential role for Dnmt1 in maintaining genomic stability during intestinal development and the establishment of intestinal crypts.
2015-05-29 | GSE67363 | GEO
Project description:Background: Wnt signaling maintains the undifferentiated state of intestinal crypt progenitor cells by inducing the formation of nuclear TCF4/beta-catenin complexes. In colorectal cancer, activating mutations in Wnt pathway components cause inappropriate activation of TCF4/beta-catenin -driven transcription. Despite the passage of a decade after the discovery of TCF4 and beta-catenin as the molecular effectors of the Wnt signal, few transcriptional activators essential and unique to the regulation of this transcription program have been found. Methodology/Principal Findings: Using proteomics, we identified the leukemia-associated Mllt10/Af10 and the methyltransferase Dot1l, as Tcf4/beta-catenin interactors in mouse small intestinal crypts. Mllt10/Af10-Dot1l, essential for transcription elongation, are recruited to Wnt target genes in a beta-catenin -dependent manner, resulting in H3K79 methylation over their coding regions in vivo in proliferative crypts of mouse small intestine, in colorectal cancer and Wnt-inducible HEK293T cells. Depletion of MLLT10/AF10 in colorectal cancer and Wnt-inducible HEK293T cells followed by expression array analysis identifies MLLT10/AF10 and DOT1L as essential activators dedicated to Wnt target gene regulation. In contrast, previously published b-catenin coactivators p300 and beta-catenin displayed a more pleiotropic target gene expression profile controlling Wnt and other pathways. tcf4, mllt10/af10 and dot1l are co-expressed in Wnt-driven tissues in zebrafish and essential for Wnt-reporter activity. Intestinal differentiation defects in apc-mutant zebrafish can be rescued by depletion of Mllt10 and Dot1l, establishing these genes as activators downstream of Apc in Wnt target gene activation in vivo. Morpholino-depletion of mllt10/af10-dot1l in zebrafish results in defects in intestinal homeostasis and a significant reduction in the in vivo expression of direct Wnt target genes and in the number of proliferative intestinal epithelial cells. Conclusions/Significance: We conclude that Mllt10/Af10-Dot1l are essential, dedicated activators of Wnt-dependent transcription, critical for maintenance of intestinal proliferation and homeostasis. The methyltransferase Dot1l may present an attractive candidate for drug targeting in colorectal cancer. 6 samples for Ls174T cells: si-b-catenin against si-control and dyeswap of it, si-control, si-MLLT10, si-BRG1 and si-P300 are hybridized against common reference RNA; 6 samples of HEK293T cells: Wnt3A or control medium (CM) induction for 9 hours, si-MLLT10, si-DOT1L, si-BRG1 and si-P300 upon 9 hour Wnt3A induction are all hybridized against common reference RNA
2010-04-20 | E-GEOD-21367 | biostudies-arrayexpress