Chromatin Folding Domains Disruptions by Somatic Genomic Rearrangements in Human Cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA479882 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7475912_1.fastq.gz | Fastqsanger.gz | |||
| SRR7475912_2.fastq.gz | Fastqsanger.gz | |||
| SRR7475913_1.fastq.gz | Fastqsanger.gz | |||
| SRR7475913_2.fastq.gz | Fastqsanger.gz | |||
| SRR7475914_1.fastq.gz | Fastqsanger.gz |
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Project description:Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Genes within the same folding domain demonstrate similar expression and histone-modification profiles1. Therefore, boundaries separating different domains have important roles in reinforcing the stability of these domain-wide features. Indeed, domain boundary disruptions in human genetic disorders2,3 or human cancers lead to misregulation of certain genes4,5, due to de novo enhancer exposure to promoters. However, the frequency of boundary disruptions in human cancers, and whether there are recurrently affected boundaries in specific cancer types, remains unclear. Here, to understand effects and distributions of somatic structural variations (SVs) across TADs, we utilized 288,457 high-confidence somatic structural variations from 2658 high-coverage whole genome sequencing datasets across various cancer types. We comprehensively profiled structural variations effects on the domain boundaries and the regulation of genes in human cancers. Notably, most of the TAD disruptions do not result in appreciable changes in nearby gene expression where more than 2-fold expression change was observed in only 14% of regions with the boundary deletions. In addition, we demonstrated that SV types affect TADs differently, specifically, complex rearrangements drastically change chromatin folding maps in the cancer genomes.
2020-02-05 | GSE116694 | GEO
Project description:Mammalian chromosomes are partitioned into contact domains that can be conserved as functional units in evolution. Disruptions of domains can result from perturbed CTCF, cohesin, or chromosomal rearrangements. However, to what extent domains can be created de novo has not been explored in depth. Here, using a gain-of-function approach leveraging genome editing and Hi-C, we examined whether, and how, a putative boundary element can function to organize de novo domains in the context of multiple ectopic insertion sites. We subsequently dissected the distinct roles of the CTCF binding site and the transcription start site within the insertion element in changing genome folding.
2020-03-14 | GSE137373 | GEO
Project description:Mammalian chromosomes are partitioned into contact domains that can be conserved as functional units in evolution. Disruptions of domains can result from perturbed CTCF, cohesin, or chromosomal rearrangements. However, to what extent domains can be created de novo has not been explored in depth. Here, using a gain-of-function approach leveraging genome editing and Hi-C, we examined whether, and how, a putative boundary element can function to organize de novo domains in the context of multiple ectopic insertion sites. We subsequently dissected the distinct roles of the CTCF binding site and the transcription start site within the insertion element in changing genome folding.
2020-03-14 | GSE137372 | GEO
Project description:Mammalian chromosomes are partitioned into contact domains that can be conserved as functional units in evolution. Disruptions of domains can result from perturbed CTCF, cohesin, or chromosomal rearrangements. However, to what extent domains can be created de novo has not been explored in depth. Here, using a gain-of-function approach leveraging genome editing and Hi-C, we examined whether, and how, a putative boundary element can function to organize de novo domains in the context of multiple ectopic insertion sites. We subsequently dissected the distinct roles of the CTCF binding site and the transcription start site within the insertion element in changing genome folding.
2020-03-14 | GSE137374 | GEO
Project description:Mammalian chromosomes are partitioned into contact domains that can be conserved as functional units in evolution. Disruptions of domains can result from perturbed CTCF, cohesin, or chromosomal rearrangements. However, to what extent domains can be created de novo has not been explored in depth. Here, using a gain-of-function approach leveraging genome editing and Hi-C, we examined whether, and how, a putative boundary element can function to organize de novo domains in the context of multiple ectopic insertion sites. We subsequently dissected the distinct roles of the CTCF binding site and the transcription start site within the insertion element in changing genome folding.
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Project description:Mammalian chromosomes are partitioned into contact domains that can be conserved as functional units in evolution. Disruptions of domains can result from perturbed CTCF, cohesin, or chromosomal rearrangements. However, to what extent domains can be created de novo has not been explored in depth. Here, using a gain-of-function approach leveraging genome editing and Hi-C, we examined whether, and how, a putative boundary element can function to organize de novo domains in the context of multiple ectopic insertion sites. We subsequently dissected the distinct roles of the CTCF binding site and the transcription start site within the insertion element in changing genome folding.
2020-03-14 | GSE137371 | GEO
Project description:Mammalian chromosomes are partitioned into contact domains that can be conserved as functional units in evolution. Disruptions of domains can result from perturbed CTCF, cohesin, or chromosomal rearrangements. However, to what extent domains can be created de novo has not been explored in depth. Here, using a gain-of-function approach leveraging genome editing and Hi-C, we examined whether, and how, a putative boundary element can function to organize de novo domains in the context of multiple ectopic insertion sites. We subsequently dissected the distinct roles of the CTCF binding site and the transcription start site within the insertion element in changing genome folding.
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Project description:Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
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Project description:While the protein composition of various yeast 60S ribosomal subunit assembly intermediates has been studied in detail, little is known about ribosomal RNA (rRNA) structural rearrangements that take place during early 60S assembly steps. Using a high-throughput RNA structure probing method, we provide nucleotide resolution insights into rRNA structural rearrangements during nucleolar 60S assembly. Our results suggest that many rRNA-folding steps, such as folding of 5.8S rRNA, occur at a very specific stage of assembly, and propose that downstream nuclear assembly events can only continue once 5.8S folding has been completed. Our maps of nucleotide flexibility enable making predictions about the establishment of protein-rRNA interactions, providing intriguing insights into the temporal order of protein-rRNA as well as long-range inter-domain rRNA interactions. These data argue that many distant domains in the rRNA can assemble simultaneously during early 60S assembly and underscore the enormous complexity of 60S synthesis.Ribosome biogenesis is a dynamic process that involves the ordered assembly of ribosomal proteins and numerous RNA structural rearrangements. Here the authors apply ChemModSeq, a high-throughput RNA structure probing method, to quantitatively measure changes in RNA flexibility during the nucleolar stages of 60S assembly in yeast.
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Project description:We describe a Hi-C based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorted than topologically-associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes, and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, “gene looping” factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome and our findings provide insights into the machinery underlying chromosome compaction. Chromatin is fragmented by Mnase, subsequenct nucleosomal end repair, and a modified two-step method for purfiying ligation products. Using Illumina paired-end sequencing maps Micro-C library and generates nucleosome resolution contact maps. The readme.txt file contains additional description of how each processed data file was generated.
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