Landscape of enhancer disruption and functional screen in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA865698 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20791621_1.fastq.gz | Fastqsanger.gz | |||
| SRR20791621_2.fastq.gz | Fastqsanger.gz | |||
| SRR20789793.fastq.gz | Fastqsanger.gz | |||
| SRR20789794.fastq.gz | Fastqsanger.gz | |||
| SRR20789795.fastq.gz | Fastqsanger.gz |
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Project description:Landscape of enhancer disruption and functional screen in melanoma [4C-seq]
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Project description:The high mutation rate across the whole melanoma genome provides a major challenge in stratifying true driver events from the background mutations. Many non-coding recurrent events, such as those occurred in enhancer, can shape tumor evolution, emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. Here, we leveraged 297 melanoma whole-genome sequencing (WGS) samples to prioritize highly recurrent regions (HRRs). By performing a genome-scale CRISPR interference (CRISPRi) screen on HRR-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers revealed many known and hidden mechanisms underlying melanoma development. We demonstrated that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A and another distal enhancer was able to sustain PTEN tumor-suppressive potential via long-range interaction. Our study established a catalogue of crucial enhancers and their target genes in melanoma development and progression, which illuminates the identification of novel mechanism of dysregulation for melanoma driver genes and new therapeutic targeting strategy.
2023-10-11 | GSE210423 | GEO
Project description:The high mutation rate across the whole melanoma genome provides a major challenge in stratifying true driver events from the background mutations. Many non-coding recurrent events, such as those occurred in enhancer, can shape tumor evolution, emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. Here, we leveraged 297 melanoma whole-genome sequencing (WGS) samples to prioritize highly recurrent regions (HRRs). By performing a genome-scale CRISPR interference (CRISPRi) screen on HRR-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers revealed many known and hidden mechanisms underlying melanoma development. We demonstrated that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A and another distal enhancer was able to sustain PTEN tumor-suppressive potential via long-range interaction. Our study established a catalogue of crucial enhancers and their target genes in melanoma development and progression, which illuminates the identification of novel mechanism of dysregulation for melanoma driver genes and new therapeutic targeting strategy.
2023-10-11 | GSE210422 | GEO
Project description:The high mutation rate across the whole melanoma genome provides a major challenge in stratifying true driver events from the background mutations. Many non-coding recurrent events, such as those occurred in enhancer, can shape tumor evolution, emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. Here, we leveraged 297 melanoma whole-genome sequencing (WGS) samples to prioritize highly recurrent regions (HRRs). By performing a genome-scale CRISPR interference (CRISPRi) screen on HRR-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers revealed many known and hidden mechanisms underlying melanoma development. We demonstrated that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A and another distal enhancer was able to sustain PTEN tumor-suppressive potential via long-range interaction. Our study established a catalogue of crucial enhancers and their target genes in melanoma development and progression, which illuminates the identification of novel mechanism of dysregulation for melanoma driver genes and new therapeutic targeting strategy.
2023-10-11 | GSE210421 | GEO
Project description:BackgroundThe high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma.ResultsHere, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions.ConclusionsOur study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.
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Project description:Enhancers play key roles in gene regulation. However, comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Through gene regulatory network modeling, we identified that dynamic cell state transitions, a critical missing component in prevalent enhancer discovery strategies, can be utilized to improve the cells’ sensitivity to enhancer perturbation. Guided by the modeling results, we performed a mid-transition CRISPRi-based enhancer screen utilizing human embryonic stem cell definitive endoderm differentiation as a dynamic transition system. The screen discovered a comprehensive set of enhancers (4 to 9 per locus) for each of the core lineage-specifying transcription factors (TFs), including many enhancers with weak to moderate effects. Integrating the screening results with enhancer activity measurements (ATAC-seq, H3K27ac ChIP-seq) and three-dimensional enhancer-promoter interaction information (CTCF looping, Hi-C), we were able to develop a CTCF loop-constrained Interaction Activity (CIA) model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Together, our dynamic network-guided enhancer screen and the CIA enhancer prediction model provide generalizable strategies for sensitive and more comprehensive enhancer discovery in both normal and pathological cell state transitions.
2023-06-17 | PXD043070 | Pride
Project description:We carried out CRISPR-Cas9 functional screen focused on AP-1 bound enhancers that are activated upon oncogenic stress. The screen discovered Enh.AP1.OIS1 - an enhancer bound by AP1 that is required for activation of oncogene-induced senescence (OIS) response. We applied RNA-seq analysis to RASG12V-activated BJ cells transduced with either sgRNAs targeting AP-1 bound enhancer (sgRNA-69 or sgRNA71), or sgRNA targeting the target gene FOXF1 or non-targeting control sgRNA (sgNT)
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