Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues

Nature Genetics
Gilad LandanAmos Tanay

Abstract

DNA methylation has been comprehensively profiled in normal and cancer cells, but the dynamics that form, maintain and reprogram differentially methylated regions remain enigmatic. Here, we show that methylation patterns within populations of cells from individual somatic tissues are heterogeneous and polymorphic. Using in vitro evolution of immortalized fibroblasts for over 300 generations, we track the dynamics of polymorphic methylation at regions developing significant differential methylation on average. The data indicate that changes in population-averaged methylation occur through a stochastic process that generates a stream of local and uncorrelated methylation aberrations. Despite the stochastic nature of the process, nearly deterministic epigenetic remodeling emerges on average at loci that lose or gain resistance to methylation accumulation. Changes in the susceptibility to methylation accumulation are correlated with changes in histone modification and CTCF occupancy. Characterizing epigenomic polymorphism within cell populations is therefore critical to understanding methylation dynamics in normal and cancer cells.

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Related Concepts

Ctcf protein, mouse
Fibroblasts
Genetic Polymorphism
Repressor Molecules
Tumor Cells, Cultured
Gene Expression Regulation, Neoplastic
Sequence Determinations, DNA
CpG Clusters
DNA Methylation
Epigenesis, Genetic

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