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| Status |
Public on Dec 12, 2021 |
| Title |
Epigenetic therapy suppresses tumour growth by rewiring ER-mediated long-range chromatin interactions in ER+ endocrine-resistant breast cancer [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Here we investigate the impact of epigenetic therapy with Decitabine in endocrine-resistant ER+ breast cancer by using patient-derived xenograft (PDX) models. Decitabine treatment restrained tumour growth, inhibited cell proliferation and resulted in significant loss of DNA methylation, particularly at enhancers and repetitive elements. Systematic integration of matched in situ Hi-C / PCHi-C, EPIC, RNA-seq and ChIP–seq datasets revealed widespread differences in epigenome regulation and enhancer-promoter communication with Decitabine. We find that loss of DNA methylation with Decitabine strongly affects the open (A) and closed (B) compartment structure and TAD boundary insulation. Our study identified and focused on key DNA methylation-dependent, enhancer ER binding sites that are activated in Decitabine-treated PDX tumours, enabling direct interactions between promoters and multiple distal enhancers, inducing expression of ER target genes and pathways. Overall, we demonstrate that epigenetic therapy inhibits tumour progression through to rewiring of ER-mediated 3D chromatin interactions and transcriptome programs. Our findings suggest that targeting the 3D epigenome with epigenetic therapies represents a promising strategy for anti-cancer treatment in ER+ endocrine resistant breast cancer patients.
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| Overall design |
To understand the Decitabine-induced molecular changes driving tumour regression on a global scale, we used in situ Hi-C to generate genome-wide 3D genome maps of PDX breast tumours treated with Decitabine. At the same time, we examined the genome-wide DNA methylation (EPIC Microarrays), promoter-anchored interactome (Promoter Capture Hi-C (PCHi-C)), transcription factor binding (ER and FOXA1 ChIP-seq) and gene expression (RNA-seq) in the same tumours.
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| Web link |
https://doi.org/10.1101/2021.06.21.449340
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| |
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| Contributor(s) |
Achinger-Kawecka J |
| Citation(s) |
38448820 |
| |
| Submission date |
Mar 29, 2021 |
| Last update date |
Mar 13, 2024 |
| Contact name |
Joanna Achinger-Kawecka |
| E-mail(s) |
j.achinger@garvan.org.au
|
| Organization name |
Garvan Institute of Medical Research
|
| Street address |
384 Victoria Street
|
| City |
Darlinghurst |
| State/province |
NSW |
| ZIP/Postal code |
2010 |
| Country |
Australia |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (16)
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| This SubSeries is part of SuperSeries: |
| GSE171074 |
The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer |
|
| Relations |
| BioProject |
PRJNA718303 |
| SRA |
SRP312612 |
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