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Genetic disruption of Ctcf destabilizes DNA methylation

ABSTRACT: Ctcf heterozygous knockout mice are susceptible to neoplasia in a broad range of tissues, including lymphoma, endometrial cancer, and non-small cell lung cancer. Retention of the wild type Ctcf allele in these tumors establishes CTCF as a haploinsufficient tumor suppressor gene. Both human tumors and normal murine tissues with CTCF disruption are characterized by genome-wide differences in DNA methylation relative to CTCF wild type tissues, indicating even modest disruption of CTCF broadly destabilizes DNA methylation in vivo. This cross species functional analysis identifies CTCF as a commonly mutated tumor suppressor gene and establishes a central role for DNA methylation stability in tumor suppression.

ORGANISM(S): Mus musculus

PROVIDER: GSE48975 | GEO | 2014/07/30

SECONDARY ACCESSION(S): PRJNA212502

REPOSITORIES: GEO

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Genetic disruption of Ctcf destabilizes DNA methylation

Project description:Ctcf heterozygous knockout mice are susceptible to neoplasia in a broad range of tissues, including lymphoma, endometrial cancer, and non-small cell lung cancer. Retention of the wild type Ctcf allele in these tumors establishes CTCF as a haploinsufficient tumor suppressor gene. Both human tumors and normal murine tissues with CTCF disruption are characterized by genome-wide differences in DNA methylation relative to CTCF wild type tissues, indicating even modest disruption of CTCF broadly destabilizes DNA methylation in vivo. This cross species functional analysis identifies CTCF as a commonly mutated tumor suppressor gene and establishes a central role for DNA methylation stability in tumor suppression. RRBS sequencing of transgenic Ctcf heterozygous mice and wild-type litter mate whole lung tissue.

2014-07-30 | E-GEOD-48975 | biostudies-arrayexpress

Mus musculus

Project description:Genetic disruption of Ctcf destabilizes DNA methylation

| PRJNA212502 | ENA

Srf destabilizes cell identity

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A novel metastasis–associated lncRNA destabilizes p21 through cooperative interactions with the NF90/NF45 complex

Project description:Long non-coding RNAs (lncRNA) have emerged as important regulators of gene expression at both the transcriptional and post-transcriptional levels. While altered expressions of lncRNAs have been observed in breast cancer (BCa) development, their roles in BCa progression and metastasis are still poorly understood. To identify novel BCa-associated lncRNA candidates, we have employed a high-density SNP array based approach to uncover lncRNA genes at intergenic region that are aberrantly expressed in BCa. Here we report the role of a novel lncRNA, LincIN, in breast cancer progression and metastasis. High levels of LincIN expression are frequently observed in tumors compared to adjacent normal tissues, and are strongly associated with aggressive breast cancers. Importantly, analysis of The Cancer Genome Atlas (TCGA) data further suggested that high LincIN expression was associated with poor overall survival in patients with breast cancer (P<0.05). Our gain-and-loss experiments demonstrate that LincIN play a role in tumor cell migration and invasion and knockdown of LincIN diminishes tumor cell invasion in vitro and lung metastasis in a mouse xenograft model. We also identified a LincIN-binding protein complex, NF90/NF45, through which LincIN destabilizes tumor suppressor p21 mRNA post-transcriptionally and thereby represses its protein expression. In summary, our findings delineated an oncogenic role of LincIN in breast tumor progression-metastasis, and mechanistically uncovered its cooperative actions with NF90/NF45 in regulating tumor suppressor gene expression at the post-transcriptional level.

2017-03-01 | GSE79214 | GEO

Altered topology drives oncogenic programs in SDH-deficient GIST

Project description:<p>Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.</p>

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CTCF promotes epithelial ovarian cancer metastasis by broadly controlling the expression of metastasis-associated genes

Project description:CCCTC-binding factor (CTCF) is an 11 zinc fingers transcription factor that functions as both an oncogenic and tumor suppressor, depending on the cancer types, through epigenetic regulation. Epigenetic regulation including DNA methylation and histone modifications are critically involved in cancer metastasis. We then hypothesized that CTCF might play a vital role in epithelial ovarian cancer metastasis. Firstly, we found that CTCF expression was elevated in ovarian cancer tissues compared to non-tumor tissues. The elevated expression of CTCF predicts poor prognosis of ovarian cancer patients. Then, we revealed that CTCF knockdown significantly inhibited the migration, invasion and metastasis of ovarian cancer cells, although it had no effect on cell proliferation and tumor growth, which have been demonstrated with both in vitro and in vivo experiments. More importantly, we observed a higher CTCF expression in metastatic lesions than that in primary lesions from ovarian cancer patients. Mechanically, PCR array demonstrated that CTCF might regulate a series of metastasis associated genes, including CTBP1, SERPINE1 and SRC. Finally, we observed positive correlations between CTCF expression and those three genes in epithelial ovarian cancer specimens. In conclusion, this study demonstrates that CTCF is an oncogene in ovarian cancer to promote tumor metastasis through broadly controlling the expression of metastasis-associated genes. Our findings suggest CTCF could be a novel drug target to treat ovarian cancer by interfering with cancer cell metastasis.

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Ctcf Haploinsufficiency Mediates Intron Retention in A Tissue-specific Manner

Project description:CCCTC binding-factor (CTCF) is a master regulator of gene transcription and chromatin organization with occupancy at tens of thousands of DNA target sites genome-wide. CTCF is essential for embryonic development and somatic cell viability and has been well-characterized as a haploinsufficient tumor suppressor. Increasing evidence demonstrates CTCF as a key player in several alternative splicing (AS) regulatory mechanisms, including transcription elongation, transcriptional regulation of splicing factors, DNA methylation, histone modification and chromatin architecture. However, the genome-wide impact of Ctcf haploinsufficiency on AS has not been investigated. We performed a transcriptomic analysis on multiple tissues from a Ctcf hemizygous (Ctcf+/-) mouse model to examine the effect of Ctcf haploinsufficiency on gene expression and AS. Distinct tissue-specific differences in gene expression were observed in Ctcf+/- mice compared to wildtype mice. While exon skipping was the most abundant form of AS in all tissues, we observed a surprisingly large number of increased intron retention (IR) events in Ctcf+/- liver and kidney. Increased IR in liver affected genes involved in cytoskeletal organization, splicing- and metabolic-related processes. This study provides further evidence for Ctcf dose-dependent and tissue-specific regulation of gene expression and AS. Our data provide a strong foundation for elucidating the mechanistic role of CTCF in AS regulation and its biological consequences.

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