Integrative Hi-C maps of pancreatic cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE149103 | GEO | 2021/08/11
REPOSITORIES: GEO
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Project description:The three-dimensional (3D) organization of the genome within the cell nucleus contributes to cell-specific gene expression in different cell types1. High-throughput 3CM-bM-^@M-^Sderived methods have revealed that the genome is segmented into contiguous topologically associating domains (TADs), which help to orchestrate gene expression changes during differentiation and development2-5. Using ChIP-Seq, Hi-C and 3D modelling techniques, we reveal that TADs regulate the rapid gene expression changes induced by progestin in T47D breast cancer cells. In response to the hormone, TADs maintain their borders and operate as discrete regulatory units in which the majority of the genes are either transcriptionally activated or repressed. Additionally, the epigenetic signatures of the TADs are coordinately modified by hormone in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodelling are accompanied by structural changes that are distinct for activated or repressed TADs. Integrative 3D modelling revealed that TADs are structurally expanded if active and compacted if repressed, and that this is accompanied by differential changes in accessibility. We thus propose that TADs function as M-bM-^@M-^\regulonsM-bM-^@M-^] to enable spatially proximal genes to be coordinately transcribed in response to hormones. T47D-MTVL human breast cancer cells were incubated with the progestin R5020 for different times at 37M-BM-:C and prepared for ChIP-Seq or Hi-C according published protocols
2014-10-06 | E-GEOD-53463 | biostudies-arrayexpress
Project description:The three-dimensional organization of chromosomes is tightly related to their biological function. Both imaging and chromosome conformation capture studies have revealed several layers of organization, including segregation into active and inactive compartments at the megabase scale, and partitioning into domains (TADs) and associated loops at the sub-megabase scale. Yet, it remains unclear how these layers of genome organization form, interact with one another, and contribute to or result from genome activities. TADs seem to have critical roles in regulating gene expression by promoting or preventing interactions between promoters and distant cis-acting regulatory elements, and different architectural proteins, including cohesin, have been proposed to play central roles in their formation. But so far, experimental depletions of these proteins have resulted in marginal changes in chromosome organization. Here, we show that deletion of the cohesin-loading factor, Nipbl, leads to loss of chromosome-associated cohesin and results in dramatic genome reorganization. TADs and associated loops vanish globally, even in the absence of transcriptional changes. In contrast, segregation into compartments is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the independent action of two distinct mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartment regions, defined by the underlying chromatin state; and 2) cohesin-dependent formation of TADs possibly by the recently proposed loop extrusion mechanism, enabling long-range and target-specific activity of promiscuous enhancers. The interplay between these mechanisms creates an architecture that is more complex than a simple structural hierarchy and can be central to guiding normal development.
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Project description:Chromosomes in proliferating metazoan cells undergo dramatic structural metamorphoses every cell cycle, alternating between a highly condensed mitotic structure facilitating chromosome segregation, and a decondensed interphase structure accommodating transcription, gene silencing and DNA replication. These cyclical structural transformations have been evident under the microscope for over a century, but their molecular-level analysis is still lacking. Here we use single-cell Hi-C to study chromosome conformations in thousands of individual cells, and discover a continuum of cis-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological domains (TADs), contact insulation and long-range loops, all defined by ensemble Hi-C maps, are governed by distinct cell cycle dynamics. In particular, DNA replication correlates with build-up of compartments and reduction in TAD insulation, while loops are generally stable from G1 through S and G2. Analysing whole genome 3D structural models using haploid cell data, we discover a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data creates an essential new paradigm for the re-interpretation of chromosome conformation maps through the prism of the cell cycle.
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Project description:Mammalian genomes are organized into compartments, topologically-associating domains (TADs) and loops to facilitate gene regulation and other chromosomal functions. Compartments are formed by nucleosomal interactions, but how TADs and loops are generated is unknown. It has been proposed that cohesin forms these structures by extruding loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here we show that cohesin suppresses compartments but is essential for TADs and loops, that CTCF defines their boundaries, and that WAPL and its PDS5 binding partners control the length of chromatin loops. In the absence of WAPL and PDS5 proteins, cohesin passes CTCF sites with increased frequency, forms extended chromatin loops, accumulates in axial chromosomal positions (vermicelli) and condenses chromosomes to an extent normally only seen in mitosis. These results show that cohesin has an essential genome-wide function in mediating long-range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
2017-12-07 | GSE102884 | GEO
Project description:Inactivating mutations of genes encoding the cohesin complex are common in a wide range of human cancers. STAG2 is the most commonly mutated subunit. Here we report the impact of stable correction of endogenous, naturally occurring STAG2 mutations on gene expression, 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme. Correction of mutant STAG2 significantly altered the expression of ~10% of all expressed genes. The genes most highly regulated by STAG2 (e.g. FGF7, c-KIT, MAGE tumor antigens) were virtually all upregulated in STAG2-mutant cells. Hi-C revealed that ~3% of A/B compartments switched after STAG2 correction, and confirmed prior findings that STAG2 is dispensable for maintenance of Topologically Associating Domains (TADs). The size and strength of thousands of chromatin loops were altered by STAG2 correction, a subset of which controlled the expression of adjacent genes. Loops specific to STAG2-mutant cells and tumors were very large, supporting prior findings that STAG1-containing cohesin complexes have greater loop extrusion processivity than STAG2-containing cohesin complexes, and suggesting that long loops may be a generalizable feature of STAG2-mutant cancers. Finally, STAG2-regulated chromatin loops were enriched for the H3K27me3 Polycomb epigenetic mark, revealing that inactivation of STAG2 can activate Polycomb signaling in GBM. Together these findings illuminate the landscape of STAG2-regulated genes, A/B compartments, chromatin loops, and pathways in GBM, providing important clues into the still mysterious mechanism of STAG2 tumor suppression in human cancer.
2024-05-07 | GSE240343 | GEO
Project description:Mammalian chromosomes are folded into intricate hierarchies of interaction domains, within which topologically associating domains (TADs) and CTCF-associated loops partition the physical interactions between regulatory sequences. Current understanding of chromosome folding largely relies on chromosome conformation capture (3C)-based experiments, where chromosomal interactions are detected as ligation products after crosslinking of chromatin. To measure chromosome structure in vivo, quantitatively and without relying on crosslinking and ligation, we have implemented a modified version of damID named damC. DamC combines DNA-methylation based detection of chromosomal interactions with next-generation sequencing and a biophysical model of methylation kinetics. DamC performed in mouse embryonic stem cells provides the first in vivo validation of the existence of TADs and CTCF loops and confirms 3C-based measurements of the scaling of contact probabilities. Combining damC with transposon-mediated genomic engineering shows that new loops can be formed between ectopically introduced and endogenous CTCF sites, which alters the partitioning of physical interactions within TADs. This orthogonal approach to 3C provides the first crosslinking- and ligation-free validation of the existence of key structural features of mammalian chromosomes and provides novel insights into how chromosome structure within TADs can be manipulated.
2019-06-03 | PXD013507 | Pride
Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. BS-Seq of 4 patients (A13, A38, A124 and A125). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets). Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates. Patient A124 included 2 primary tumors and 1 normal pancreas.
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Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. RNA-Seq of 2 patients (A13 and A38). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets), and 6AN treated and DMSO control samples. Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates.
2016-10-24 | E-GEOD-63124 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is a set of heterogeneous myeloid malignancies hallmarked by mutations in epigenetic modifiers, transcription factors and kinases that can cause epigenetic reshaping. It is unclear whether those mutations drive chromatin 3D structure alteration and contribute to oncogenic dysregulation in AML. By performing Hi-C and whole genome sequencing in 21 primary AML and healthy donors’ samples, we identified recurrent AML- or subtype-specific alteration of compartments, TADs, and chromatin loops. To study the impact on gene regulation, we performed RNA-Seq, ATAC-Seq and CUT&TAG for CTCF, H3K27ac, and H3K27me3 in the same samples. We observed dysregulation of many AML-related genes, represented by MYCN, MEIS1, WT1, ERG, MYC GATA3, BCL11B and IKZF2, intimately linked to the recurrent gain of loops and switch of compartment or TAD, alongside acquisition of AML-specific enhancer or repressor. Further, we profiled structure variations using WGS and Hi-C data to reconstruct the cancer 3D genome, by which we identified structure variation-induced neo-loops and enhancer-hijacking events. Furthermore, through conducting whole genome bisulfite sequencing in patient samples, we found altered methylation correlated with A/B compartment switch, and loss of CTCF insulation due to hypermethylation, leading to extensive gain of loops in AML. By treating the AML cells with DNA hypomethylation agent 5-azacytidine, the altered chromatin structure and gene expression can be restored, with switched compartment reverted and gained loops dissociated, alongside compromised AML cell proliferation, overall providing insights into AML treatment through therapeutic restoration of chromatin structure.
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