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

ABSTRACT: 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.

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE296957 | 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 [ATAC-seq]

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 | GSE297077 | GEO

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

Mapping genetic modifiers of epimutation rates identifies VIM2/4 as dosage-sensitive negative regulators of CG methylation maintenance [RNAseq_VIM2/4]

2026-07-18 | GSE333206 | GEO

Rate, spectrum, and evolutionary dynamics of spontaneous epimutations

Project description:Stochastic changes in cytosine methylation are a source of heritable epigenetic and phenotypic diversity in plants. Using the model plant Arabidopsis thaliana, we derive robust estimates of the rate at which methylation is spontaneously gained (forward epimutation) or lost (backward epimutation) at individual cytosines and construct a comprehensive picture of the epimutation landscape in this species. We demonstrate that the dynamic interplay between forward and backward epimutations is modulated by genomic context and show that subtle contextual differences have profoundly shaped patterns of methylation diversity in A. thaliana natural populations over evolutionary timescales. Theoretical arguments indicate that the epimutation rates reported here are high enough to rapidly uncouple genetic from epigenetic variation, but low enough for new epialleles to sustain long-term selection responses. Our results provide new insights into methylome evolution and its population-level consequences. MethylC-seq of Arabidopsis thaliana

2015-05-13 | E-GEOD-64463 | biostudies-arrayexpress

Rate, spectrum, and evolutionary dynamics of spontaneous epimutations

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Centromeres are hotspots of DNA methylation epimutations that are transmitted and occur at high rates in a filamentous fungus

Project description:Epimutations are changes in chromatin modifications, such as DNA methylation or histone modifications. Some of these epigenetic changes can be inherited for several generations, and thus could contribute to evolutionary processes. Estimates of epimutation rates now exists in a few species, but epigenetic mechanism are not conserved across all life, and epigenetic marks funtion differently in different species. To understand the properties of epimutations in fungi, we performed a mutation accumulation experiment with the filamentous fungus Neurospora crassa and investigated spontaneous DNA methylation and trimethylation of lysine 9 on histone H3 (H3K9me3) changes in the mutation accumulation lines. We observed that centromeric regions are hotspots of spontaneous DNA methylation changes in N. crassa. In these hotspot regions, DNA methylation changes were transmitted across mitoses, but changes occurring in euchromatin were not maintained. The rate of DNA methylation changes was more than 10 000-fold faster than the genetic mutation rate. We did not observe spontaneous changes in H3K9me3 that were transmitted across mitoses. Our results show that while spontaneous epimutations occur in this species, they occur predominantly in gene poor heterochromatic regions, so their impact for evolutionary adaptation may be limited.

2026-03-02 | GSE313506 | GEO

A balance of de novo and maintenance activities governs epigenetic inheritance of CG methylation in Arabidopsis transposons

Project description:Dnmt1/MET1 methyltransferases mediate the epigenetic inheritance of cytosine methylation within CG dinucleotides (mCG). These enzymes use a semiconservative mechanism previously expected to produce binary present/absent methylation patterns. However, we show here that in Arabidopsis thaliana h1ddm1 mutants, intermediate heterochromatic mCG is quantitatively associated with transposon expression and is stably inherited across many generations. We develop a mathematical model that estimates the rates of semiconservative maintenance failure and de novo methylation at each transposon, demonstrating that mCG can be stably inherited at any level via a dynamical balance of these activities. We find that DRM2 – the core methyltransferase of the RNA-directed DNA methylation pathway – catalyzes most of the heterochromatic de novo mCG, with de novo rates orders of magnitude higher than previously thought, whereas chromomethylases make smaller contributions. Our results demonstrate that mCG epigenetic inheritance in plant heterochromatin is highly dynamic, with CG sites frequently switching methylation states.

2023-02-17 | GSE197718 | GEO

Primary constitutional MLH1 epimutations: a focal epigenetic event [FFPE data sets]

Project description:Background: Constitutional MLH1 epimutations are characterized by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterization of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Methods: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients and 41 healthy controls, were analyzed by Infinium Human Methylation 450K beadchip, and targeted molecular techniques were used to characterize the MLH1 epimutation in carriers and their inheritance pattern. Results: No nucleotide or structural variants were identified in-cis on the epimutated allele in ten carriers, in which intergenerational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Conclusion: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterization is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.

2017-11-28 | GSE107352 | GEO

Primary constitutional MLH1 epimutations: a focal epigenetic event [blood data sets]

2017-11-28 | GSE107351 | GEO

Transgenerational Stability of the Arabidopsis Epigenome Is Coordinated by CG Methylation

Project description:Maintenance of CG methylation (mCG) patterns is essential for chromatin-mediated epigenetic regulation of transcription in plants and mammals. Using successive generations of an Arabidopsis thaliana mutant deficient in maintaining mCG, we found that mCG loss triggered genome-wide activation of alternative epigenetic mechanisms. However, these mechanisms involving RNA-directed DNA methylation, inhibiting expression of DNA demethylases, and retargeting of histone H3K9 methylation act in a stochastic and uncoordinated fashion. As a result, new and aberrant epigenetic patterns were progressively formed over several plant generations in the absence of mCG. Interestingly, the unconventional redistribution of epigenetic marks was necessary to ‘rescue’ the loss of mCG, since mutant plants impaired in rescue activities were severely dwarfed and sterile. Our results provide evidence that mCG is a central coordinator of epigenetic memory that secures stable transgenerational inheritance in plants. Keywords: DNA methylation profiling, epigenetic inheritance, mCIP, H3K9 methylation, RdDM, demethylase expression

2007-06-27 | GSE8279 | GEO

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