3D genome organization, transcription and aberrant DNA replication contribute to genome instability at fragile sites
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA631844 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11774300.fastq.gz | Fastqsanger.gz | |||
| SRR11774301.fastq.gz | Fastqsanger.gz | |||
| SRR11774302.fastq.gz | Fastqsanger.gz | |||
| SRR11774303.fastq.gz | Fastqsanger.gz | |||
| SRR11774304.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 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.
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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 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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