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Mapping genetic modifiers of epimutation rates identifies VIM2/4 as dosage-sensitive negative regulators of CG methylation maintenance

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE297108 | GEO | 2026/07/18

REPOSITORIES: GEO

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Mapping genetic modifiers of epimutation rates identifies VIM2/4 as dosage-sensitive negative regulators of CG methylation maintenance [WGBS]

Project description:Spontaneous epimutations—stochastic changes in cytosine methylation—can persist across generations in plants and are thought to contribute to phenotypic variation. Although epimutations are increasingly studied for their potential long-term effects, it remains unclear why their accumulation varies across genotypes. Here, we tracked DNA methylation across nine generations in ~400 mutation accumulation lineages derived from ~70 Arabidopsis Ler × Cvi recombinant inbred lines. Treating epimutation rates as quantitative molecular traits, we mapped a major QTL to a Cvi-derived deletion near VIM2 and VIM4, two genes involved in CG methylation (mCG) maintenance. We show that this deletion rapidly reduces genome-wide methylation to a lower steady-state and compromises mCG maintenance fidelity across generations, resulting in a ~1.5-fold increase in epimutation rates. Genotypes with elevated rates exhibited accelerated epigenetic drift and phenotypic divergence. Our findings support a punctuated-equilibrium model of mCG evolution, in which sudden disruptions to methylation homeostasis can destabilize epigenetic inheritance over longer time-scales.

2026-07-18 | GSE296957 | GEO

Mapping genetic modifiers of epimutation rates identifies VIM2/4 as dosage-sensitive negative regulators of CG methylation maintenance [ATAC-seq]

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Mapping genetic modifiers of epimutation rates identifies VIM2/4 as dosage-sensitive negative regulators of CG methylation maintenance [WGBS_VIM2/4]

Project description:Spontaneous epimutations are stochastic gains and losses of cytosine methylation that arise from imperfect maintenance across cell divisions. At CG sites, such epimutations can be inherited across generations in plants and constitute a major source of CG methylation (mCG) diversity. However, why the fidelity of mCG inheritance varies among genotypes, and how this variation relates to steady-state mCG levels, remain poorly understood. Here we tracked DNA methylation over ten generations in ~400 mutation-accumulation lines derived from ~70 Arabidopsis thaliana Ler × Cvi recombinant inbred founders. By treating methylation gain and loss rates as quantitative molecular traits, we mapped a major-effect locus to a Cvi-derived deletion between VIM2 and VIM4, two components of the MET1-dependent mCG maintenance pathway. Lines carrying this deletion showed elevated VIM2/4 expression, a rapid shift of genome-wide mCG toward a lower steady state, and reduced fidelity of methylation inheritance across generations. Complementary overexpression and loss-of-function experiments identify VIM2 and VIM4 as dosage-sensitive negative regulators of mCG maintenance, in contrast to the canonical positive role of VIM-family proteins in CG methylation. Together, our results support a punctuated-equilibrium model of DNA methylome evolution, in which naturally segregating modifiers of mCG homeostasis can produce abrupt shifts in methylation state and alter the rate at which heritable epigenetic variation accumulates in plant genomes.

2026-07-18 | GSE333205 | GEO