CTCF/cohesin-binding sites mutated in cancer
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR906805.fastq.gz | Fastqsanger.gz | |||
| ERR906806.fastq.gz | Fastqsanger.gz | |||
| ERR906807.fastq.gz | Fastqsanger.gz | |||
| ERR906808.fastq.gz | Fastqsanger.gz | |||
| ERR906809.fastq.gz | Fastqsanger.gz |
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Project description:Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.
| EGAS00001003010 | EGA
Project description:CCCTC-binding factor (CTCF) and cohesin play a significant role in the formation of chromatin loops and topologically associating domains (TADs), which influence gene expression and DNA replication. CTCF/cohesin-binding sites (CBSs) present at the loop anchors and TAD boundaries are frequently mutated in cancer; however, the molecular mechanisms underlying this remain unclear. Here, we investigate whether the binding of CTCF/cohesin on DNA imposes constraints on DNA replication, leading to replication stress and genomic instability. Our results reveal that CTCF and cohesin remain cobound to DNA during replication (S phase) in cancer cells (HeLa). Further, examination of replication stress through ChIP-seq of the DNA damage response/repair proteins (MRE11, STN1, FANCD2, γH2AX, RAD51 and ATM) showed high enrichment of these proteins at CBSs (as compared to their immediate flanking regions and control sites) and positively correlated with the binding strength of CTCF/cohesin at CBSs in the S phase. Moreover, analysis of somatic mutations from cancer genomes supports that the enrichment of mutations at CBSs is significantly higher in samples harbouring somatic copy number deletion in MRE11 and STN1 compared to wild-type samples. Together, these results demonstrate that the co-binding of CTCF/cohesin on the DNA during the S phase causes replication stress and DNA strand breaks, and this could lead to genome instability at CBSs observed in cancer.
2025-03-22 | GSE292153 | GEO
Project description:CTCF binding sites are frequently mutated in cancer, but how these mutations accumulate and whether they broadly perturb CTCF binding is not well understood. We report that skin cancers exhibit a highly-specific asymmetric mutation pattern within CTCF motifs attributable to ultraviolet irradiation and differential nucleotide excision repair (NER). CTCF binding site mutations form independent of replication timing and are enriched at sites of CTCF/cohesin complex binding, suggesting a role for cohesin in stabilizing CTCF-DNA binding and impairing NER. Performing CTCF ChIP-seq in a melanoma cell-line, we show CTCF binding site mutations to be functional by demonstrating allele-specific reduction of CTCF binding to mutant alleles. While topologically-associating domains with mutated CTCF anchors in melanoma contain differentially-expressed cancer-associated genes, CTCF motif mutations appear generally under neutral selection. However, the frequency and potential functional impact of such mutations in melanoma highlights the need to consider their impact on cellular phenotype in individual genomes.
2016-12-13 | GSE81945 | GEO
Project description:ChIP-seq for CTCF and Rad21 in 3 week old mouse brain from reciprocal BxC and CxB crosses. One biological replicate of each. Examination of CTCF and Cohesin binding sites in neonetal mouse brain
2013-06-20 | E-GEOD-35140 | biostudies-arrayexpress
Project description:Identification of cohesin (Rad21) and CTCF binding sites in ~2% of the mouse genome in B3 pre-B cells stably expressing FLAG-tagged Rad21 using anti-FLAG (Sigma F3165) and anti-CTCF (Upstate 07729) antibodies
2008-01-31 | E-TABM-401 | biostudies-arrayexpress
Project description:Mammalian chromosomes are partitioned into topologically associating domains (TADs) by the loop-extrusion activity of cohesin that is blocked at specific DNA sites bound by CTCF. Chromosome structure inside TADs is highly variable in single cells, yet little is known about its temporal dynamics, how it influences the rates and durations of chromosomal contacts, and how it depends on CTCF and cohesin. To address these questions we combine two quantitative live-cell imaging strategies that minimize locus-specific confounding effects. We show that loop extrusion by cohesin globally reduces the mobility of the chromatin fiber in living cells, while also increasing the rates of formation and durations of contacts between sequences inside the same TAD. Quantitative analysis of high-resolution microscopy data reveals that contacts assemble and disassemble frequently in the course of the cell cycle, and become substantially more frequent and longer in the presence of convergent CTCF sites. Comparison with polymer modeling additionally reveals that cohesin-mediated CTCF loops last around 10 minutes on average. Our data support the notion that chromosome structure within TADs is highly dynamic and provide a quantitative framework for understanding the principles that link chromosome structure to biological function.
2022-02-27 | GSE197237 | GEO
Project description:CTCF sites are abundant in the genomes of diverse species but their function is enigmatic. We used chromosome conformation capture to determine long-range interactions among CTCF/cohesin sites over 2 Mb on human chromosome 11 encompassing the β-globin locus and flanking olfactory receptor genes. Although CTCF occupies these sites in both erythroid K562 cells and fibroblast 293T cells, the long-range interaction frequencies among the sites are highly cell type specific, revealing a more densely clustered organization in the absence of globin gene activity. Both CTCF and cohesins are required for the cell-type-specific chromatin conformation. Furthermore, loss of the organizational loops in K562 cells through reduction of CTCF with shRNA results in acquisition of repressive histone marks in the globin locus and reduces globin gene expression, whereas silent flanking olfactory receptor genes are unaffected. These results support a genome-wide role for CTCF/cohesin sites through loop formation that both influences transcription and contributes to cell-type-specific chromatin organization and function. Comparison of CTCF binding in K562 and 293T cells using ChIP-chip. 3 replicates each cell type, ChIP and input DNA for each replicate.
2011-01-13 | E-GEOD-26507 | biostudies-arrayexpress
Project description:Replication stress underlies genomic instability at CTCF/cohesin-binding sites in cancer
| PRJNA1237290 | ENA
Project description:Recent studies of genome-wide chromatin interactions have revealed that the human genome is partitioned into many self-associating topological domains. The boundary sequences are enriched for binding sites of CTCF and the cohesin complex, implicating these two factors in the establishment or maintenance of topological domains. To determine the role of cohesin and CTCF in higher order chromatin architecture in human cells, we proteolytically cleaved the cohesin complex from interphase chromatin and examined changes in chromosomal organization as well as transcriptome. We observed a general loss of local chromosomal interactions upon disruption of cohesin complex, but the topological domains remain intact. However, we found that depletion of CTCF by RNA interference in these cells not only reduced intra-domain interactions but also increased inter-domain interactions. Further more, distinct groups of genes become mis-regulated upon depletion of cohesin and CTCF. Taken together, these observations suggest that CTCF and cohesin contribute in different ways to chromatin organization and gene regulation. Hi-C and mRNA-seq experiments in Cohesin and CTCF depleted HEK293 cells
2013-12-16 | E-GEOD-44267 | biostudies-arrayexpress
Project description:CCCTC-binding factor (CTCF) is an architectural protein involved in the three-dimensional organization of chromatin. In this study, we systematically assayed the 3D genomic contact profiles of hundreds of CTCF binding sites in multiple tissues with high-resolution 4C-seq. We find both developmentally stable and dynamic chromatin loops. As recently reported, our data also suggest that chromatin loops preferentially form between CTCF binding sites oriented in a convergent manner. To directly test this, we used CRISPR-Cas9 genome editing to delete core CTCF binding sites in three loci, including the CTCF site in the Sox2 super-enhancer. In all instances, CTCF and cohesin recruitment were lost, and chromatin loops with distal CTCF sites were disrupted or destabilized. Re-insertion of oppositely oriented CTCF recognition sequences restored CTCF and cohesin recruitment, but did not re-establish chromatin loops. We conclude that CTCF binding polarity plays a functional role in the formation of higher order chromatin structure. 4C-seq was performed on a large number of viewpoints in E14 embryonic stem cells, neural precursor cells and primary fetal liver cells
2015-10-29 | E-GEOD-72539 | biostudies-arrayexpress