A dynamic multi-compartmental model of DNA methylation with demonstrable predictive value in hematological malignancies

McGovern, Andrew P, Powell, Benjamin E and Chevassut, Timothy J T (2012) A dynamic multi-compartmental model of DNA methylation with demonstrable predictive value in hematological malignancies. Journal of Theoretical Biology, 310 (7). pp. 14-20. ISSN 1095-8541

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Abstract

Recent advances have highlighted the central role of DNA methylation in leukemogenesis and have led to clinical trials of epigenetic therapy, notably hypomethylating agents, in myelodysplasia and acute myeloid leukemia. However, despite these advances, our understanding of the dynamic regulation of the methylome remains poor. We have attempted to address this shortcoming by producing a dynamic, six-compartmental model of DNA methylation levels based on the activity of the Dnmt methyltransferase proteins. In addition, the model incorporates the recently discovered Tet family proteins which enzymatically convert methylcytosine to hydroxymethylcytosine. A set of first order, partial differential equations comprise the model and were solved via numerical integration. The model is able to predict the relative abundances of unmethylated, hemimethylated, fully methylated, and hydroxymethylated CpG dyads in the DNA of cells with fully functional Dnmt and Tet proteins. In addition, the model accurately predicts the experimentally measured changes in these abundances with disruption of Dnmt function. Furthermore, the model reveals the mechanism whereby CpG islands are maintained in a hypomethylated state via local modulation of Dnmt and Tet activities without any requirement for active demethylation. We conclude that this model provides an accurate depiction of the major epigenetic processes involving modification of DNA.

Item Type: Article
Keywords: CpG island; Methylcytosine; Hydroxymethylcytosine; DNA methyltransferase (Dnmt); Tet protein
Schools and Departments: Brighton and Sussex Medical School > Clinical and Laboratory Investigation
Subjects: R Medicine
Depositing User: Patricia Butler
Date Deposited: 01 Nov 2012 10:03
Last Modified: 01 Nov 2012 10:03
URI: http://sro.sussex.ac.uk/id/eprint/41770
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