3D genome organization, transcription and aberrant DNA replication contribute to genome instability at fragile sites
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA632744 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11788747.fastq.gz | Fastqsanger.gz | |||
| SRR11788748.fastq.gz | Fastqsanger.gz | |||
| SRR11788749.fastq.gz | Fastqsanger.gz | |||
| SRR11788750.fastq.gz | Fastqsanger.gz | |||
| SRR11788751.fastq.gz | Fastqsanger.gz |
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Project description:3D genome organization, transcription and aberrant DNA replication contribute to genome instability at fragile sites
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Project description:Common fragile sites (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features characterizing CFSs have been associated with their instability, however, these features are prevalent across the genome and do not account for all known CFSs. Here we explored the transcriptional profile and DNA replication timing under mild replication stress in the context of the 3D genome organization. We report the analysis of nascent RNA-seq for high-throughput profiling of gene expression in human fibroblasts (BJ-hTERT), grown with or without aphidicolin, a DNA polymerase inhibitor used to induce CFS expression. We find that aphidicolin treatment does not affect the transcriptional program. However, large expressed genes are susceptible to replication timing delay under stress. We further study the mechanism leading to recurrent chromosomal instability at CFSs and find that the 3D genome organization underlies fragility at large expressed genes. We report a fragility signature at the core of CFSs comprised of a large expressed gene spanning over a TAD-boundary with delayed DNA replication. The fragility signature allows for mapping of the core fragile site and the identification of novel fragile sites in BJ cells.
2020-06-08 | GSE150354 | GEO
Project description:Common fragile sites (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features characterizing CFSs have been associated with their instability, however, these features are prevalent across the genome and do not account for all known CFSs. Here we explored the DNA replication timing (RT) and transcriptional profile under mild replication stress in the context of the 3D genome organization. We report the analysis of DNA replication timing profiling of human fibroblasts (BJ-hTERT), grown with or without aphidicolin, a DNA polymerase inhibitor used to induce CFS expression. We find that aphidicolin treatment affects the RT of a small portion of the genome. However, CFSs are enriched for delayed RT regions under stress. We further study the mechanism leading to recurrent chromosomal instability at CFSs and find that the 3D genome organization underlies fragility at RT delayed large expressed genes. We report a fragility signature at the core of CFSs comprised of delayed replication of large expressed gene spanning over a TAD-boundary. The fragility signature allows for mapping of the core fragile site and the identification of novel fragile sites in BJ cells.
2020-06-09 | GSE150543 | GEO
Project description:Common fragile sites (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features were suggested to underlie CFS instability, however, these features are prevalent across the genome. Therefore, the molecular mechanisms underlying CFS instability remain unclear. Here, we explore the transcriptional profile and DNA replication timing (RT) under mild replication stress in the context of the 3D genome organization. The results reveal a fragility signature, comprised of a TAD boundary overlapping a highly transcribed large gene with APH-induced RT-delay. This signature enables precise mapping of core fragility regions in known CFSs and identification of novel fragile sites. CFS stability may be compromised by incomplete DNA replication and repair in TAD boundaries core fragility regions leading to genomic instability. The identified fragility signature will allow for a more comprehensive mapping of CFSs and pave the way for investigating mechanisms promoting genomic instability in cancer.
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Project description:Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is caused by an expansion of CGG repeats located in the 5Õ untranslated region (UTR) of the FMR1 gene, leading to hypermethylation and silencing of this locus. While the dramatic increase in DNA methylation (DNAm) of the FMR1 full mutation allele is well documented, the extent that these changes affect DNAm throughout the entire gene and the rest of the genome remains unexplored. Here, we examine the genome-wide methylation in peripheral blood (N = 9) as well as induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls (N = 53 and 9, respectively) and find the expected significant DNAm differences in the FMR1 promoter and 5Õ UTR, but also that these changes inversely persist throughout the FMR1 gene body. Importantly, we find there are no additional differential methylated loci (DML) throughout the remainder of the genome, indicating that the aberrant methylation of the FMR1 in FXS is locus-specific and does not change DNAm genome-wide. This study provides a comprehensive methylation profile of FXS and refines mechanistic considerations of FMR1 silencing. A total of 62 blood (53 controls + 9 Fragile X) samples analyzed using a linear regression model.
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Project description:DNA double-strand breaks (DSBs) in B lymphocytes arise stochastically during replication or as a result of targeted DNA damage by activation-induced cytidine deaminase (AID). Here we identify recurrent, early replicating, and AID-independent DNA lesions, termed early replication fragile sites (ERFSs), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFSs colocalize with highly expressed gene clusters and are enriched for repetitive elements and CpG dinucleotides. Although distinct from late-replicating common fragile sites (CFS), the stability of ERFSs and CFSs is similarly dependent on the replication-stress response kinase ATR. ERFSs break spontaneously during replication, but their fragility is increased by hydroxyurea, ATR inhibition, or deregulated c-Myc expression. Moreover, greater than 50% of recurrent amplifications/deletions in human diffuse large B cell lymphoma map to ERFSs. In summary, we have identified a source of spontaneous DNA lesions that drives instability at preferred genomic sites.
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Project description:Mutations in the SETX gene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases Ataxia with Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells and SETX knockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased RNA polymerase II pausing events (transcription stress) near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. Aberrant R-loops were resolved by transcription-coupled repair (TCR), in reactions dependent upon the Cockayne Syndrome protein CSB. We found that CSB was required for the recruitment of the TCR endonucleases XPG and XPF, and recombination factors to target and resolve transcription bubbles containing R-loops and promote genomic instability. These results show that cells derived from individuals with Ataxia with Oculomotor Apraxia 2 exhibit transcription stress giving rise to genome-wide chromosomal fragility, termed transcription stress-induced fragile sites (TSFS), in transcribed regions of the mammalian genome.
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Project description:Mutations in the SETX gene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases Ataxia with Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells and SETX knockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased RNA polymerase II pausing events (transcription stress) near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. Aberrant R-loops were resolved by transcription-coupled repair (TCR), in reactions dependent upon the Cockayne Syndrome protein CSB. We found that CSB was required for the recruitment of the TCR endonucleases XPG and XPF, and recombination factors to target and resolve transcription bubbles containing R-loops and promote genomic instability. These results show that cells derived from individuals with Ataxia with Oculomotor Apraxia 2 exhibit transcription stress giving rise to genome-wide chromosomal fragility, termed transcription stress-induced fragile sites (TSFS), in transcribed regions of the mammalian genome.
2021-04-29 | GSE153577 | GEO
Project description:Mutations in the SETX gene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases Ataxia with Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells and SETX knockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased RNA polymerase II pausing events (transcription stress) near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. Aberrant R-loops were resolved by transcription-coupled repair (TCR), in reactions dependent upon the Cockayne Syndrome protein CSB. We found that CSB was required for the recruitment of the TCR endonucleases XPG and XPF, and recombination factors to target and resolve transcription bubbles containing R-loops and promote genomic instability. These results show that cells derived from individuals with Ataxia with Oculomotor Apraxia 2 exhibit transcription stress giving rise to genome-wide chromosomal fragility, termed transcription stress-induced fragile sites (TSFS), in transcribed regions of the mammalian genome.
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