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Updated: Jul 4, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Reconstruction of cell-specific models capturing the influence of metabolism on DNA methylation in cancer
Tânia Barata1, Vítor Pereira2, Ricardo Pires das Neves3
1CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-517 Coimbra, Portugal.
Abstract:
The imbalance of epigenetic regulatory mechanisms such as DNA methylation, which can promote aberrant gene expression profiles without affecting the DNA sequence, may cause the deregulation of signaling, regulatory, and metabolic processes, contributing to a cancerous phenotype. Since some metabolites are substrates and cofactors of epigenetic regulators, their availability can be affected by characteristic cancer cell metabolic shifts, feeding cancer onset and progression through epigenetic deregulation. Hence, there is a need to study the influence of cancer metabolic reprogramming in DNA methylation to design new effective treatments. In this study, a generic Genome-Scale Metabolic Model (GSMM) of a human cell, integrating DNA methylation or demethylation reactions, was obtained and used for the reconstruction of Genome-Scale Metabolic Models enhanced with Enzymatic Constraints using Kinetic and Omics data (GECKOs) of 31 cancer cell lines. Furthermore, cell-line-specific DNA methylation levels were included in the models, as coefficients of a DNA composition pseudo-reaction, to depict the influence of metabolism over global DNA methylation in each of the cancer cell lines. Flux simulations demonstrated the ability of these models to provide simulated fluxes of exchange reactions similar to the equivalent experimentally measured uptake/secretion rates and to make good functional predictions. In addition, simulations found metabolic pathways, reactions and enzymes directly or inversely associated with the gene promoter methylation. Two potential candidates for targeted cancer epigenetic therapy were identified.
Insights
Cancer cell metabolism influences DNA methylation, impacting gene expression and cancer development. This study models this link to identify new epigenetic therapy targets.
Area of Science:
- Biochemistry
- Systems Biology
- Cancer Biology
Background:
- Epigenetic deregulation, particularly DNA methylation imbalances, contributes to cancer by altering gene expression.
- Cancer cell metabolic reprogramming affects metabolite availability, influencing epigenetic regulators and promoting cancer progression.
- Understanding the interplay between cancer metabolism and DNA methylation is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the influence of cancer metabolic reprogramming on DNA methylation.
- To develop predictive models linking metabolic shifts to DNA methylation patterns in cancer.
- To identify potential therapeutic targets for cancer epigenetic therapy.
Main Methods:
- Reconstruction of Genome-Scale Metabolic Models (GSMMs) for 31 cancer cell lines, incorporating DNA methylation/demethylation reactions.
- Integration of enzymatic constraints using Kinetic and Omics data (GECKOs) into the GSMMs.
- Inclusion of cell-line-specific DNA methylation levels to model metabolic influence on global DNA methylation.
Main Results:
- Validated GSMMs accurately predicted experimental metabolic exchange rates and functional cell behavior.
- Identified specific metabolic pathways, reactions, and enzymes associated with gene promoter methylation.
- Discovered two promising candidate targets for epigenetic cancer therapy.
Conclusions:
- Metabolic reprogramming significantly influences DNA methylation in cancer cells.
- The developed models provide a powerful tool for studying cancer metabolism-epigenetics interactions.
- This research opens avenues for targeted epigenetic therapies based on metabolic vulnerabilities.
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