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Systematical identification of cell-specificity of CTCF-gene binding based on epigenetic modifications
Abstract:
The CCCTC-binding factor (CTCF) mediates transcriptional regulation and implicates epigenetic modifications in cancers. However, the systematically unveiling inverse regulatory relationship between CTCF and epigenetic modifications still remains unclear, especially the mechanism by which histone modification mediates CTCF binding. Here, we developed a systematic approach to investigate how epigenetic changes affect CTCF binding. Through integration analysis of CTCF binding in 30 cell lines, we concluded that CTCF generally binds with higher intensity in normal cell lines than that in cancers, and higher intensity in genome regions closed to transcription start sites. To facilitate the better understanding of their associations, we constructed linear mixed-effect models to analyze the effects of the epigenetic modifications on CTCF binding in four cancer cell lines and six normal cell lines, and identified seven epigenetic modifications as potential epigenetic patterns that influence CTCF binding intensity in promoter regions and six epigenetic modifications in enhancer regions. Further analysis of the effects in different locations revealed that the epigenetic regulation of CTCF binding was location-specific and cancer cell line-specific. Moreover, H3K4me2 and H3K9ac showed the potential association with immune regulation of disease. Taken together, our method can contribute to improve the understanding of the epigenetic regulation of CTCF binding and provide potential therapeutic targets for treating tumors associated with CTCF.
Insights
The CCCTC-binding factor (CTCF) shows altered binding in cancer cells compared to normal cells, influenced by specific epigenetic modifications. Understanding these epigenetic changes offers potential therapeutic targets for CTCF-associated tumors.
Area of Science:
- Genomics
- Epigenetics
- Cancer Biology
Background:
- The CCCTC-binding factor (CTCF) is crucial for transcriptional regulation and epigenetic modifications in cancer.
- The precise mechanisms by which histone modifications influence CTCF binding remain incompletely understood.
Purpose of the Study:
- To systematically investigate how epigenetic changes affect CTCF binding.
- To identify specific epigenetic modifications that regulate CTCF binding intensity.
- To explore the location- and cancer-specific nature of epigenetic regulation on CTCF binding.
Main Methods:
- Integration analysis of CTCF binding data across 30 cell lines.
- Development of linear mixed-effect models to assess epigenetic modification effects on CTCF binding.
- Analysis of CTCF binding intensity in promoter and enhancer regions.
Main Results:
- CTCF binding intensity is generally higher in normal cell lines than in cancer cell lines.
- CTCF binding is more intense in genomic regions near transcription start sites.
- Seven and six epigenetic modifications were identified as influencing CTCF binding in promoter and enhancer regions, respectively.
- Epigenetic regulation of CTCF binding demonstrated location-specific and cancer cell line-specific patterns.
- H3K4me2 and H3K9ac were associated with immune regulation in disease.
Conclusions:
- The developed systematic approach enhances understanding of epigenetic regulation of CTCF binding.
- Identified epigenetic modifications and their specific regulatory patterns offer potential therapeutic targets for CTCF-related cancers.
- Findings highlight the intricate, context-dependent relationship between epigenetics and CTCF binding in cancer development.
