CTCF Loss Potentiates P53 Mediated Gene Transcription in Breast Tissue
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ABSTRACT:
PROVIDER: PRJNA900176 | ENA |
REPOSITORIES: ENA
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Project description:A single copy loss of CTCF is found in about 50% of breast cancer patients. Based on clinical TCGA data we hypothesized that the loss of CTCF may potentiate TP53 target gene expression in patients. Using MCF10A cells as a model, we deleted a single copy of CTCF using CRISPR/Cas9. We found, using qPCR and RNA-seq, that cells carrying low CTCF displayed an enhanced TP53 response after exposure to chemotherapeutics. Using ATAC-seq, we aimed to explore whether the elevated induction of TP53 target gene transcription was associated with changes in open or closed chromatin structure. Specifically, we were interested in comparing chromatin accessibility at TP53 target genes within MCF10A CTCF +/- cells compared to control cells following the induction of DNA damage (6uM cisplatin for 8h). We discovered that accessibility of the transcription start site is associated with heightened gene expression in CTCF+/- compared to the control. Interestingly, for a subset of TP53 response genes, there is increased accessibility on both transcriptional start sites and termination sites following the induction of DNA damage. The importance of chromatin accessibility at these two regions is still under investigation. Additionally, accessible gene regions at both sites also appear to have greater enrichment within TADS in the CTCF+/- cell compared to the control. We propose that the increased accessibility of TP53 target genes following damage represents a mechanism enhancing the efficacy of the TP53-regulated DNA damage response.
2023-11-10 | GSE217698 | GEO
Project description:POGZ loss increases TGFβ signaling and potentiates TNBC metastasis
| PRJNA1039840 | ENA
Project description:The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription. Here we systematically integrated multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, CRISPR-Cas9 survival dropout screening, time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewired genome-wide chromatin accessibility. Increased accessible chromatin regions were largely located adjacent to CTCF-binding sites at promoter regions and insulator sites and were associated with enhanced transcription of nearby genes. In addition, we used CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners in regulating downstream gene expression. We successfully identified 40 candidates, including multiple established partners (i.e., MYC) supported by all layers of evidence. Interestingly, many CTCF co-regulators (e.g., YY1, ZBTB7A) that have evident alterations of respective downstream gene expression do not show changes at their expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription. This study highlights CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation
2021-07-04 | PXD026484 | Pride
Project description:BACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. METHODS: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. RESULTS: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of beta-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. CONCLUSION: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development. Samples were collected from genetically modified mice. Gene recombination was induced using IP administration of beta-napthoflavone.
2015-06-25 | E-GEOD-70262 | biostudies-arrayexpress
Project description:Epigenetic mechanisms often play an important role in driving tumor progression towards metastasis. It is less clear that deregulation of chromatin architecture, including topologically associated domains (TADS), contributes to cancer progression. CTCF is a central regulator of three dimensional chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains obscure. We find that the reduced pools of CTCF in hemizygous models potentiates cell invasion. Underlying this phenotype is the activation of oncogenic networks including the PI3K signaling cascade, which presents therapeutic vulnerabilities, especially to mTOR inhibitors. Deregulation of these oncogenic pathways is largely due to the loss of CTCF insulation, allowing a reorganization of long-range chromatin contacts at the subTAD level that is associated with aberrant programming of H3K27 acetylation at enhancer/promoter regions. Thus, lowered CTCF levels lead to chromatin reorganization facilitating pro-invasive transcriptional programs.
2022-01-01 | GSE183380 | GEO
Project description:Epigenetic mechanisms often play an important role in driving tumor progression towards metastasis. It is less clear that deregulation of chromatin architecture, including topologically associated domains (TADS), contributes to cancer progression. CTCF is a central regulator of three dimensional chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains obscure. We find that the reduced pools of CTCF in hemizygous models potentiates cell invasion. Underlying this phenotype is the activation of oncogenic networks including the PI3K signaling cascade, which presents therapeutic vulnerabilities, especially to mTOR inhibitors. Deregulation of these oncogenic pathways is largely due to the loss of CTCF insulation, allowing a reorganization of long-range chromatin contacts at the subTAD level that is associated with aberrant programming of H3K27 acetylation at enhancer/promoter regions. Thus, lowered CTCF levels lead to chromatin reorganization facilitating pro-invasive transcriptional programs.
2022-01-01 | GSE183378 | GEO
Project description:Epigenetic mechanisms often play an important role in driving tumor progression towards metastasis. It is less clear that deregulation of chromatin architecture, including topologically associated domains (TADS), contributes to cancer progression. CTCF is a central regulator of three dimensional chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains obscure. We find that the reduced pools of CTCF in hemizygous models potentiates cell invasion. Underlying this phenotype is the activation of oncogenic networks including the PI3K signaling cascade, which presents therapeutic vulnerabilities, especially to mTOR inhibitors. Deregulation of these oncogenic pathways is largely due to the loss of CTCF insulation, allowing a reorganization of long-range chromatin contacts at the subTAD level that is associated with aberrant programming of H3K27 acetylation at enhancer/promoter regions. Thus, lowered CTCF levels lead to chromatin reorganization facilitating pro-invasive transcriptional programs.
2022-01-01 | GSE183379 | GEO
Project description:Loss of p53 dictates Wnt-dependent systemic inflammation in breast cancer
| PRJNA448734 | ENA
Project description:Cancer-associated inflammatory processes in the tumour microenvironment, as well as systemically, are strongly linked with poor disease outcome in cancer patients. For most human solid tumour types, high systemic neutrophil-to-lymphocyte ratios (NLR) are associated with increased metastasis and poor overall survival and recent experimental studies have demonstrated a causal relationship between neutrophils and metastasis formation. However, to date, the cancer cell-intrinsic mechanisms dictating the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Using a panel of 16 distinct genetically engineered mouse models (GEMMs) for breast cancer, we demonstrate that tumour cell-intrinsic loss of p53 changes the phenotype and function of macrophages in the microenvironment, leading to activation of a systemic inflammatory cascade that drives neutrophil expansion. Mechanistically, p53 loss in cancer cells induces secretion of Wnt ligands that act in a paracrine fashion to stimulate IL-1b production from tumour-associated macrophages. Intratumoural IL-1β production stimulates an inflammatory cascade leading to the systemic accumulation of neutrophils. Pharmacological and genetic blockade of cancer cell-derived Wnt secretion reverses IL-1β expression by macrophages and subsequent systemic neutrophilic inflammation. Collectively, using pre-clinical mouse models for breast cancer, we demonstrate a novel mechanistic link between loss of p53 in cancer cells, Wnt ligand secretion and systemic immune activation. This illustrates the importance of cancer cell-intrinsic genetic aberrations in dictating cancer-associated inflammation. These insights set the stage for personalized immune intervention strategies for cancer patients.
2019-05-20 | GSE112665 | GEO
Project description:Genomic Retargeting of Tumor Suppressors p53 and CTCF Promotes Oncogenesis
| PRJNA589049 | ENA