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Updated: Dec 19, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
Nathan A Damaschke1, Joseph Gawdzik1, Mele Avilla1
1Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Background:
The chromatin insulator CCCTC-binding factor (CTCF) displays tissue-specific DNA binding sites that regulate transcription and chromatin organization. Despite evidence linking CTCF to the protection of epigenetic states through barrier insulation, the impact of CTCF loss on genome-wide DNA methylation sites in human cancer remains undefined.
Results:
Here, we demonstrate that prostate and breast cancers within The Cancer Genome Atlas (TCGA) exhibit frequent copy number loss of CTCF and that this loss is associated with increased DNA methylation events that occur preferentially at CTCF binding sites. CTCF sites differ among tumor types and result in tissue-specific methylation patterns with little overlap between breast and prostate cancers. DNA methylation and transcriptome profiling in vitro establish that forced downregulation of CTCF leads to spatially distinct DNA hypermethylation surrounding CTCF binding sites, loss of CTCF binding, and decreased gene expression that is also seen in human tumors. DNA methylation inhibition reverses loss of expression at these CTCF-regulated genes.
Conclusion:
These findings establish CTCF loss as a major mediator in directing localized DNA hypermethylation events in a tissue-specific fashion and further support its role as a driver of the cancer phenotype.
Insights
Loss of the CCCTC-binding factor (CTCF) in cancer leads to tissue-specific DNA hypermethylation at CTCF binding sites, impacting gene expression and driving cancer progression.
Area of Science:
- Epigenetics
- Cancer Biology
- Genomics
Background:
- The CCCTC-binding factor (CTCF) is a key regulator of transcription and chromatin organization with tissue-specific DNA binding sites.
- CTCF is known to protect epigenetic states via barrier insulation, but its role in genome-wide DNA methylation in human cancer is unclear.
Purpose of the Study:
- To investigate the impact of CTCF loss on DNA methylation patterns in human cancers.
- To determine if CTCF loss contributes to cancer phenotype through epigenetic alterations.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) data for prostate and breast cancers.
- DNA methylation and transcriptome profiling in vitro.
- Forced downregulation of CTCF in cell models.
Main Results:
- Prostate and breast cancers show frequent copy number loss of CTCF, associated with increased DNA methylation at CTCF binding sites.
- CTCF binding sites and resulting methylation patterns are tissue-specific between breast and prostate cancers.
- CTCF downregulation causes localized DNA hypermethylation, loss of CTCF binding, decreased gene expression, and reversed expression upon methylation inhibition.
Conclusions:
- CTCF loss is a significant driver of localized, tissue-specific DNA hypermethylation in cancer.
- CTCF loss contributes to the cancer phenotype by altering epigenetic states and gene expression.
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