A topological atlas reveals layers of genome reorganization in colorectal cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE133928 | GEO | 2020/08/24
REPOSITORIES: GEO
Similar Datasets
Project description:A topological atlas reveals layers of genome reorganization in colorectal cancer
| PRJNA553150 | ENA
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>
| phs001906 | dbGaP
Project description:One elusive aspect of the chromosome architecture is how it constrains the DNA topology. Nucleosomes stabilise negative DNA supercoils by restraining a DNA linking number difference (∆Lk) of about -1.26. However, whether this capacity is uniform across the genome is unknown. Here, we calculated the ∆Lk restrained by over 4000 nucleosomes in yeast cells. To achieve this, we placed each nucleosome in a circular minichromosome and performed Topo-seq, a high-throughput procedure to inspect the topology of circular DNA libraries in one gel electrophoresis. We found that nucleosomes inherently restrain distinct ∆Lk values depending on their genomic origin. Nucleosome DNA topologies differ at gene bodies (∆Lk=-1.29), intergenic regions (∆Lk=-1.23), rDNA genes (∆Lk=-1.24) and telomeric regions (∆Lk=-1.07). Nucleosomes near the transcription start and termination sites also exhibit singular DNA topologies. Our findings demonstrate that nucleosome DNA topology is imprinted by its native chromatin context and persists when the nucleosome is relocated.
2023-06-05 | GSE228623 | GEO
Project description:The human genome is folded into regulatory units termed ‘topologically-associated domains’ (TADs), within which the majority of gene-enhancer interactions occur. Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries3,4. However, the impact of individual insulators on enhancer-gene interactions and transcription remains poorly understood. Here, we investigate epigenome editing strategies for perturbing individual CTCF insulators and evaluating consequent effects on genome topology and transcription. We show that fusions of catalytically-inactive Cas9 (dCas9) to transcriptional repressors (dCas9-KRAB) and DNA methyltransferases (dCas9-DNMT3A, dCas9-DNMT3A3L) can selectively displace CTCF from specific insulators, but only when precisely targeted to the cognate motif. We further demonstrate that stable, mitotically-heritable insulator disruption can be achieved through combinatorial hit-and-run epigenome editing with dCas9-KRAB and dCas9-DNMT3A3L. Finally, we apply these strategies to activate PDGFRA expression in glioblastoma stem cells, thus simulating an insulator loss mechanism implicated in brain tumorigenesis. Our study provides strategies for stably modifying genome organization and gene activity without altering the underlying DNA sequence.
2019-08-07 | GSE121998 | GEO
Project description:Methylation profiling in colorectal cancer : adjacent normal tissue vs colon tumor tissue indirect comparison experiment : CRD(common reference DNA) vs tumor-adjacent normal, CRD vs Colon tumor
2012-03-10 | E-GEOD-36380 | biostudies-arrayexpress
Project description:We performed RNAi knockdown experiments on 7 different signal transduction components of the Wnt pathway in HCT116 colon cancer cells and prepared RNA libraries from the poly-adenylated fraction of the RNA. SOLiD sequencing of strand-specific, barcoded transcriptome libraries yielded expression profiles allowing us to extract common pathway signatures and enabeling us to perform susequent nested effects modelling. the resulting pathway models yields new insight in the pathway topology in colon cancer.
2014-04-18 | E-MTAB-651 | biostudies-arrayexpress
Project description: Not available
| S-EPMC3163272 | biostudies-literature
Project description:Histone H3 lysine 27 trimethylation in adult differentiated colon associated to cancer DNA hypermethylation
2009-03-18 | E-TABM-629 | biostudies-arrayexpress
Project description:Genome topology is tied to R-loop formation and genome stability. However, the regulatory mechanism remains to be elucidated. By establishing a system to sense the connections between R-loops and genome topology states, we show that inhibiting DNA topoisomerase 1 (TOP1i) triggers the global increase of R-loops (called topoR-loops) and DNA damages, which are exacerbated in the DNA damage repair-compromised mutant atm. Further suppressor screen identifies a mutation in POL2A, the catalytic subunit of DNA polymerase ?, liberating the TOP1i-induced topoR-loop accumulation and genome instability in atm. Additionally, we find a highly conserved junction domain between the exonuclease and polymerase domains in POL2A that is required for modulating topoR-loops near DNA replication origins and facilitating faithful DNA replication. Our results suggest that DNA replication is in concert with genome topological states to fine-tune R-loops and thereby maintain genome integrity, revealing a presumably conserved regulatory mechanism of TOP1i resistance in chemotherapy for ATM-deficient cancers.
2023-11-03 | GSE216170 | GEO
Project description:Genetic and epigenetic alterations are a fundamental aspect of colorectal cancer formation. There is considerable heterogeneity between colorectal cancers regarding the mutations and methylated genes they carry, and this heterogeneity may arise early in the polyp-cancer sequence. However, our understanding of the epigenetic alterations and gene mutations in colon adenomas and their relation to colorectal cancer is incomplete. Thus, we have assessed the methylome in normal colon mucosa, tubular adenomas, and colorectal adenocarcinomas and have determined the relationship of these findings between adenomas and cancer in the colon. Genome-wide alterations in DNA methylation were found in the normal colon mucosa adjacent to colorectal cancer, tubular adenomas, and colorectal cancer. Three subgroups of CRCs and two subgroups of adenomas were identified on the basis of their DNA methylation patterns. The adenomas separated into a high-frequency methylation class (Adenoma-H) and a low-frequency methylation class. The adenoma-H polyps have a methylated DNA signature similar to non-CIMP CRCs, whereas those of the Adenoma-L class have a similar methylation pattern to normal colon mucosa. The CpGs that account for these signatures are located in intragenic/intergenic regions, which suggests that these two groups of adenomas arise from different stem cell populations. We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon samples, 42 colon adenomas, and 64 colorectal cancers. Supplementary file 'GSE48684_Matrix_signal_intensities_1.txt.gz': includes the unmethylated and methylated signal intensities from Samples GSM1183439-GSM1183561. Supplementary file 'GSE48684_Matrix_signal_intensities_2.txt.gz': includes the unmethylated and methylated signal intensities from Samples GSM1235135-GSM1235158.
2014-09-08 | E-GEOD-48684 | biostudies-arrayexpress