Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Trancriptomic and epigenetic analyses of mouse organoids expressing BrafV600E mutation [BiSulfite-seq]

ABSTRACT: Abnormal promoter DNA hypermethylation arises early during tumorigenesis and yet its role in cancer initiation has remained underexplored. An important scenario for examining this is, BRAFV600E-mutant colon adenocarcinomas (COAD) which most often arise in the proximal colon and harbor extensive, abnormal gene promoter CpG-island methylation or the methylator phenotype (CIMP). How CIMP and BRAF-mutations specifically interact for COAD initiation has remained unclear. Using mouse colon-derived organoids, we show promoter hypermethylation spontaneously arises in wild type cells mimicking “aging like” phenotype. The silenced genes sufficiently activate the Wnt pathway, causing a stem–like state and profound differentiation block. This phenotype renders long-term cultured organoids to be rapidly susceptible to transformation by BRAFV600E with features of typical right-sided COAD. Our studies tightly link epigenetic abnormalities, suggested to arise with aging, to intestinal cell fate changes and define an “epi-driver” role for multiple abnormally silenced genes that predispose to BRAFV600E-driven colon tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE120759 | GEO | 2019/01/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcriptomic and epigenetic analyses of mouse organoids expressing BrafV600E mutation [Exome-seq]

Project description:Abnormal promoter DNA hypermethylation arises early during tumorigenesis and yet its role in cancer initiation has remained underexplored. An important scenario for examining this is, BRAFV600E-mutant colon adenocarcinomas (COAD) which most often arise in the proximal colon and harbor extensive, abnormal gene promoter CpG-island methylation or the methylator phenotype (CIMP). How CIMP and BRAF-mutations specifically interact for COAD initiation has remained unclear. Using mouse colon-derived organoids, we show promoter hypermethylation spontaneously arises in wild type cells mimicking “aging like” phenotype. The silenced genes sufficiently activate the Wnt pathway, causing a stem–like state and profound differentiation block. This phenotype renders long-term cultured organoids to be rapidly susceptible to transformation by BRAFV600E with features of typical right-sided COAD. Our studies tightly link epigenetic abnormalities, suggested to arise with aging, to intestinal cell fate changes and define an “epi-driver” role for multiple abnormally silenced genes that predispose to BRAFV600E-driven colon tumorigenesis.

2019-01-01 | GSE121672 | GEO

Trancriptomic and epigenetic analyses of mouse organoids expressing BrafV600E mutation [array]

2019-01-01 | GSE114800 | GEO

Trancriptomic and epigenetic analyses of mouse organoids expressing BrafV600E mutation [MBD-seq]

2019-01-01 | GSE114795 | GEO

DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways [BrafV637E knock-in ]

Project description:Promoter hypermethylation divides colon cancers into subtypes with and without a CpG island methylator phenotype (CIMP). Here, we performed genome-wide DNA methylation profiling of colonic normal and tumor tissues to dissect development of CpG hypermethylation in colon carcinogenesis. This identified age-environment related versus genetically driven CpG hypermethylation, the latter being associated with CIMP cancers. We found a strong association between BRAFV600E mutation and downregulation of the DNA demethylases TET1 and TET2. Expression of BRAFV600E in CIMP cancer cells suppressed TET1 transcription, which was sufficient to establish hypermethylation at CIMP genes promoters, including that of TET2. This phenotype was reverted by the BRAFV600E inhibitor vemurafenib. Thus, BRAFV600E, via impairment of cytosine de-methylation, is a genetic driver of CIMP in colon tumorigenesis.

2019-12-18 | GSE108606 | GEO

DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways [Colo320 cell line]

2019-12-18 | GSE124915 | GEO

DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways [Caco2 cell line]

2019-12-18 | GSE98533 | GEO

DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways [3 cell lines]

2019-12-18 | GSE98532 | GEO

DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways [tumor, paired normal]

2019-12-18 | GSE98531 | GEO

DNMT3B has oncogenic activity but evidence suggests that it does not promote CIMP nor cooperate with activated BRAFV600E in human intestinal cancer. (WGBS)

Project description:Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG Island Methylator Phenotype (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells are thought to respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by multiple approaches. By analysis of human TCGA data, we confirmed that expression of DNMT3B is frequently upregulated in CRC and this is often linked to amplification of the DNMT3B gene. In vitro, we found that ectopic expression of DNMT3B antagonizes BRAFV600E-induced proliferation arrest and inflammatory gene expression, two hallmarks of the tumor suppressive senescence program triggered by oncogenes in primary cells. Moreover, DNMT3B over expression decreased survival in a mouse model of BRAFV600E-induced intestinal cancer. However, in primary human cells in vitro, activated BRAFV600E repressed expression of DNMT3B and failed to induce a CIMP phenotype. Finally, a closer analysis of human TCGA data revealed that BRAFV600E mutations and CIMP are both linked to a low expression of DNMT3B. We conclude that while both BRAFV600E and DNMT3B both harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumour promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.

2020-02-18 | GSE126433 | GEO

DNMT3B has oncogenic activity but evidence suggests that it does not promote CIMP nor cooperate with activated BRAFV600E in human intestinal cancer. (RNA-Seq)

2020-02-18 | GSE126311 | GEO