Modelling DNA Methylation Dynamics

Abstract

Ireland Introduction"Epigenetics" as introduced by Conrad Waddington in 1946, is defined as a set of interactions between genes and the surrounding environment, which determines the phenotype or physical traits in an organism, (Murrell et al., 2005;Waddington, 1942). Initial research focused on genomic regions such as heterochromatin and euchromatin based on dense and relatively loose DNA packing, since these were known to contain inactive and active genes respectively, (Yasuhara et al., 2005). Subsequently, key roles of DNA methylation, Histone Modifications and other assistive proteins such as Methyl Binding Proteins (MBP) during gene expression and suppression were identified, (Baylin & Ohm, 2006;Jenuwein & Allis, 2001). An emergent and persistent view that every epigenetic event affects another, to strengthen or suppress gene expression has made this an active field of research. DNA methylation refers to the modification of DNA by addition of a methyl group to the cytosine base, and is the most stable, heritable and well conserved epigenetic change. It is introduced and maintained, (Riggs & Xiong, 2004;Ushijima et al., 2003) by an enzyme family called DNA Methyl Transferases (DNMT), (Doerfler et al., 1990). Methyl-Cytosine or "mC", often referred to as the fifth type of nucleotide plays an extremely important role in gene expression and other cellular activities. Although DM is defined a simple molecular modification, its effect, can range from altering the state of a single gene to controlling a whole section of chromosome in the human genome.The human genome is largely made of complex sequences evolved over time due to replication, mutations and insertion of foreign DNA. Based on the nucleotide distribution and functional significance, the genome has been categorized into different block of sequences, namely genes or coding and non-coding regions. A special type of sequence located near genes, in relation to spread of DNA methylation and dinucleotide frequencies are the CpG islands 1 . These islands are mostly found near the promoters, (5'end), of genes and their methylation levels are closely monitored to investigate the spread of Cancer. Useful insight on epigenetic mechanisms may be found from analysing the DNA sequence patterns or the genotype of the organism, (Gertz et al., 2011;Glass et al., 2004;Segal & Widom, 2009). Since more than 90% of DM occurs in CG dinucleotides, , knowledge of the distribution and location of CG can be utilized to understand the biological 1 DNA sequences are defined and classified as CpG islands if , (a) length of that DNA sequence >200 bp, (b) Total amount of Guanine and Cytosine nucleotides >50%, and, (c) the observed/expected ratio of CG dinucleotides for that given length of sequence, >60%, (Takai & Jones, 2002)

Recent advances in computational epigenetics

“…Phenomenological models (widely used in the physical and complexity sciences, including systems biology) 52 were developed for epigenetic mechanisms, in order to support formulation of hypotheses based on limited data, which could be later refined. Computational micromodels, such as that described, 45,53 utilized the Markov Chain Monte Carlo class of algorithms to mimic interdependence of epigenetic events through random sampling of states. Transcription information (as a function of histone modification levels and DNA methylation) permitted movement to new histone states, corresponding to associated transition probabilities, based on empirical data.…”