Modeling DNA Methylation Profiles through a Dynamic Equilibrium between Methylation and Demethylation.

Giulia De Riso,Annalisa Fierro,Lorenzo Chiariotti,Damiano Francesco Giuseppe Fiorillo,Gennaro Miele,Sergio Cocozza,Mariella Cuomo

doi:10.3390/biom10091271

Abstract

DNA methylation is a heritable epigenetic mark that plays a key role in regulating gene expression. Mathematical modeling has been extensively applied to unravel the regulatory mechanisms of this process. In this study, we aimed to investigate DNA methylation by performing a high-depth analysis of particular loci, and by subsequent modeling of the experimental results. In particular, we performed an in-deep DNA methylation profiling of two genomic loci surrounding the transcription start site of the D-Aspartate Oxidase and the D-Serine Oxidase genes in different samples (n = 51). We found evidence of cell-to-cell differences in DNA methylation status. However, these cell differences were maintained between different individuals, which indeed showed very similar DNA methylation profiles. Therefore, we hypothesized that the observed pattern of DNA methylation was the result of a dynamic balance between DNA methylation and demethylation, and that this balance was identical between individuals. We hence developed a simple mathematical model to test this hypothesis. Our model reliably captured the characteristics of the experimental data, suggesting that DNA methylation and demethylation work together in determining the methylation state of a locus. Furthermore, our model suggested that the methylation status of neighboring cytosines plays an important role in this balance.

Highlights

DNA methylation is a heritable epigenetic mark, consisting of the covalent binding of a methyl group to the 5th carbon of cytosines
We decided to analyze three sub-regions of the DDO promoter, each one having a limited number of CpGs, to ensure that all the possible epialleles would have been captured during the sequencing procedure
When analyzing the experimentally-determined DNA methylation profiles, we found that almost all the possible methylation classes were represented in all the tested conditions, suggesting that the methylation status of a certain locus differed from cell to cell

Summary

Introduction

DNA methylation is a heritable epigenetic mark, consisting of the covalent binding of a methyl group to the 5th carbon of cytosines. In mammals, this modification mainly occurs at CpG dinucleotides, which are enriched at genomic regulatory regions, including gene promoters [1,2]. The gain of DNA methylation is due to the activity of the DNA methyltransferases (DNMTs), which transfer the methyl group from the S-Adenosyl L-Methionine (SAM) to unmethylated cytosines. The de novo DNA methylation is instead mainly attributed to DNMT3a and DNMT3b, which bind both the hemimethylated and the unmethylated cytosines [2,3]

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