title: Collaboration between CpG sites is needed for stable somatic inheritance of DNA methylation states.
abstract: Inheritance of 5-methyl cytosine modification of CpG (CG/CG) DNA sequences is needed to maintain early developmental decisions in vertebrates. The standard inheritance model treats CpGs as independent, with methylated CpGs maintained by efficient methylation of hemimethylated CpGs produced after DNA replication, and unmethylated CpGs maintained by an absence of de novo methylation. By stochastic simulations of CpG islands over multiple cell cycles and systematic sampling of reaction parameters, we show that the standard model is inconsistent with many experimental observations. In contrast, dynamic collaboration between CpGs can provide strong error-tolerant somatic inheritance of both hypermethylated and hypomethylated states of a cluster of CpGs, reproducing observed stable bimodal methylation patterns. Known recruitment of methylating enzymes by methylated CpGs could provide the necessary collaboration, but we predict that recruitment of demethylating enzymes by unmethylated CpGs strengthens inheritance and allows CpG islands to remain hypomethylated within a sea of hypermethylation.
authors.affiliation: Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, DK-2100 Copenhagen, Denmark and Department of Molecular and Biomedical Sciences (Biochemistry), University of Adelaide, SA 5005, Australia.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Haerter
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lövkvist
authors.forename: Ian B
authors.initials: IB
authors.lastname: Dodd
authors.forename: Kim
authors.initials: K
authors.lastname: Sneppen
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D040582:Inheritance Patterns; D008957:Models, Genetic