Dynamics, stability and inheritance of somatic DNA methylation imprints

Abstract

Recent research highlights the role of CpG methylation in genomic imprinting, histone and chromatin modification, transcriptional regulation, and 'gene silencing' in cancer development. An unresolved issue, however, is the role of stable inheritance of factors that manage epigenetic imprints in renewing or expanding cell populations in soma. Here we propose a mathematical model of CpG methylation that is consistent with the cooperative roles of de novo and maintenance methylation. This model describes (1) the evolution of methylation imprints toward stable, yet noisy equilibria, (2) bifurcations in methylation levels, thus the dual stability of both hypo- and hypermethylated genomic regions, and (3) sporadic transitions from hypo- to hypermethylated equilibria as a result of methylation noise in a finite system of CpG sites. Our model not only affords an explanation of the persistent coexistence of these two equilibria, but also of sporadic changes of site-specific methylation levels that may alter preset epigenetic imprints in a renewing cell population.