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| Status |
Public on Jun 12, 2018 |
| Title |
Enhancer profiling in metastatic cancer [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Metastases cause the majority of cancer-related deaths. Yet, the origins of metastatic cancer phenotypes remain poorly understood. Few metastasis-specific driver mutations have been identified [1-3], raising the possibility that metastatic transcriptional programmes may emerge from perturbations in the oncogenic signalling cascades that support the development of primary tumours. Here, using genome-wide histone modification profiling, high-throughput chromatin conformation capture by Hi-C and functional analysis in human-derived metastasis models of renal and breast cancers, we identify transcriptional enhancers that drive metastatic cancer progression. We demonstrate that specific enhancers and enhancer clusters are activated in metastatic cancer cell populations. The activation status of these enhancers is associated with gene expression patterns predictive of poor patient outcome in clinical samples. CRISPRi-mediated inhibition of enhancer activity and genetic ablation of enhancer sequences demonstrated the requirement of metastasis-associated regulatory elements for metastatic colonization in vivo. We further show that metastatic cancer clones co-opt evolutionarily conserved enhancers that converge on shared metastasis driver genes, such as CXCR4. Thus, we provide functional evidence for the requirement of specific enhancers for metastatic colonization and show that metastatic traits can arise through tissue-specific commissioning of distal gene regulatory elements.
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| |
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| Overall design |
Examination of 2 different histone modifications and transcription factors in experimental model systems of metastasis.
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| |
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| Contributor(s) |
Rodrigues P, Vanharanta S |
| Citation(s) |
29875134 |
| Submission date |
Apr 20, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Sakari Vanharanta |
| E-mail(s) |
sv358@mrc-cu.cam.ac.uk
|
| Organization name |
University of Cambridge
|
| Department |
MRC Cancer Unit
|
| Lab |
Vanharanta
|
| Street address |
Box 197, Cambridge Biomedical Campus
|
| City |
Cambridge |
| ZIP/Postal code |
CB2 0XZ |
| Country |
United Kingdom |
| |
|
| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
|
| Samples (44)
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| This SubSeries is part of SuperSeries: |
| GSE98015 |
Enhancer profiling in metastatic cancer |
|
| Relations |
| BioProject |
PRJNA383670 |
| SRA |
SRP104404 |
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