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13 recordsLinked to original sources
PubMed2025

Intermediately Methylated Regions in Normal Cells Are Epimutation Hotspots in Cancer.

DNA methylation is altered in all cancers, but the mechanisms responsible for these changes are not well understood. Using data from 100 primary samples, we show that regions with intermediate methylation in normal hematopoietic cells are hotspots for stable, clonal epimutations in acute myeloid leukemia. Analysis of hematopoietic stem cell clones demonstrated that intermediate methylation at epimutation hotspots reflects random allele-specific methylation and expression at the single cell level, representing a previously unrecognized form of somatically acquired imprinting. We identified somatically imprinted regions in other tissues and show they are epimutation hotspots in other cancer types. This demonstrates that random allele-specific methylation is both a general property of normal cells, and a vulnerability that renders them susceptible to cooperating events and clonal selection during cancer.

Journal Article↗
PubMedDate not supplied

Mutations and epimutations in mammalian cells.

Early studies on heritable variation in cultured mammalian cells suggested that both mutation and epigenetic events might be involved. The importance of mutations has subsequently been fully documented, but only recently has an alternative form of inheritance been uncovered. This is based on the post-synthetic methylation of cytosine in regulatory regions of genes. The pattern of methylation is heritable, and in almost all cases studied, methylation of a region is associated with lack of gene expression. Such silent genes can be reactivated by the powerful demethylating agent 5-azacytidine (5-aza-CR). Changes in heritable DNA methylation which alter phenotype are referred to as epimutations. It now seems very likely that the well known 'functional hemizygosity' in CHO cells and other near diploid cell lines is due to the existence of one active and one silent gene at many autosomal loci. It is clear that permanent cell lines inactivate genes by de novo methylation, whereas normal diploid cells do not have this activity. This has important implications for our understanding of cellular transformation, tumor progression, and the increase in chromosome number frequently associated with these cellular changes. It is likely that both mutations and epimutations are important in the emergence of fully transformed tumorigenic cells. Agents which increase or reduce DNA methylation in cells can be regarded as epimutagens, although in many cases the mechanisms of inducing hypo- or hyper-methylation are not understood. Two exceptions are 5-aza-CR which inhibits the normal DNA maintenance methylase activity, and 5-methyldeoxycytidine triphosphate which is incorporated into cellular DNA following electroporation and has been shown to silence genes.

Animals↗
PubMed2026

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

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, remains poorly understood. Here we tracked DNA methylation over 10 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 VARIANT IN METHYLATION (VIM)2 and VIM4, two key components of the METHYLTRANSFERASE 1-dependent mCG maintenance pathway. Lines carrying this deletion showed elevated VIM2/4 (VIM2 and VIM4) expression, a rapid shift of genome-wide mCG towards a lower steady state and reduced fidelity of methylation inheritance across generations. Complementary overexpression and loss-of-function experiments identify VIM2/4 as dosage-sensitive negative regulators of mCG maintenance, in contrast to the canonical positive role of VIM-family proteins in mCG. 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.

Journal Article↗
PubMed1989

Mutations, epimutations, and the developmental programming of the maize Suppressor-mutator transposable element.

Information about the structure, function and regulation of the maize Suppressor-mutator (Spm) transposable element has emerged from the genetic and molecular characterization of both deletion mutations and an unconventional type of reversible genetic change (epimutation). The element is subject to an epigenetic mechanism that can either stably inactivate it or specify one of a variety of heritable programs of differential element expression in development. The essay explores the relationship between the Spm element's epigenetic developmental programming mechanism and the determinative events central to plant development and differentiation.

Base Sequence↗
PubMed1992

Epimutation of repeated genes in Ascobolus immersus.

Ascobolus immersus artificial gene repeats were shown previously to be subject premeiotically to both cytosine methylation and inactivation. We studied sexual progenies of strains harbouring two wild type copies of the endogenous met2 gene lying either in tandem array or at ectopic unlinked positions, by (i) investigating the methylation status, (ii) searching for mutations and (iii) analysing the inheritance of inactivation both in mitotic and sexual offspring. 100% of the 'tandem' progeny and 64% of the 'ectopic' progeny had methylated repeats and displayed gene inactivation. Similar methylation patterns involving all or most of the cytosine residues within the repeats were observed in both arrangements. The inactivated met2 copies were totally devoid of mutation, as deduced from: (i) extensive restriction site analysis and DNA sequencing; (ii) the finding that all the Met- derivatives tested reverted to prototrophy in selective conditions; and (iii) the finding that an inactivated copy of met2 stripped of its methylation through amplification in Escherichia coli regained activity when reintroduced in A.immersus. In the absence of selection, gene silencing and methylation were faithfully maintained through mitotic divisions and through five successive sexual cycles. Altogether, these data show the epimutational nature of this methylation induced premeiotically (MIP) process.

Acetyltransferases↗
PubMed2026

DNA methylome responses to biotic and abiotic stress in Arabidopsis thaliana: A multi-study analysis.

RATIONALE: Plants experience diverse biotic and abiotic stresses that can induce changes in DNA methylation. However, comparisons among existing studies are complicated by differences in analytical methods and experimental designs. We aimed to identify shared and stress-specific DNA methylation responses across studies. METHODS: We reanalysed 16 whole-genome bisulphite sequencing datasets from 13 Arabidopsis thaliana studies using a unified bioinformatics pipeline. Differentially methylated regions (DMRs) were assessed in the CG, CHG and CHH contexts and examined in relation to genes, transposable elements (TEs), Gene Ontology terms, gene-proximal TE superfamilies and epimutation-prone loci. RESULTS: Global methylation levels were generally stable, whereas the number and genomic distribution of DMRs varied according to stress type and methylation context. CG-DMRs occurred primarily in gene bodies, while CHG- and CHH-DMRs were enriched in TEs. Functional analysis identified shared stress-related processes across conditions. Gene-proximal LINE/L1, RathE1_cons and DNA/HAT elements were enriched for stress-responsive methylation changes. A subset of stress-associated CG-DMRs overlapped loci known to accumulate stable epimutations over generations. CONCLUSIONS: Standardized cross-study analysis revealed both shared and stress-specific methylation patterns. The association of stress-responsive DMRs with gene-proximal TEs and epimutation-prone loci suggests potential links among environmental responses, genome regulation and long-term epigenetic variation.

Arabidopsis thaliana↗
PubMed2026

Clinical and genetic characterization of constitutional MLH1 promoter hypermethylation: Implications for Lynch syndrome diagnosis.

PURPOSE: Constitutional MLH1 promoter hypermethylation (CMPH) is a relatively rare cause of Lynch syndrome. While most cases appear to be sporadic, some result from secondary epimutations, mainly caused by germline variants in the MLH1 promoter region. This study describes the clinical phenotype and genetic etiology of CMPH in the largest clinical cohort to date. METHODS: A retrospective analysis was conducted for 422 individuals who underwent clinical CMPH testing. Promoter sequencing was used to identify the underlying variants. Long-read sequencing further characterized MLH1 promoter methylation. RESULTS: CMPH was identified in 15.6% of the study cohort participants. Of these, 63 exhibited clinical features consistent with Lynch syndrome. The most common associated cancers were colorectal cancer, followed by endometrial cancer, breast cancer, and sebaceous neoplasms. Mendelian inheritance of CMPH was observed in 5 families in the study cohort, indicating secondary epimutations. Promoter sequencing identified 8 unique germline variants, including 3 novel variants. Methylation analysis by long-read sequencing revealed mutant allele-specific promoter methylation for these variants. CONCLUSION: Our findings provide the most comprehensive review of the clinical phenotype associated with CMPH and highlight the significant contribution of promoter variants to its etiology. These results underscore the need to include the assessment of constitutional MLH1 promoter methylation for Lynch syndrome diagnosis.

Humans↗
PubMed1992

Cell proliferation and thyroid neoplasia.

The classic experimental model of thyroid neoplasia using radiation as a mutagen followed by long-term goitrogen treatment gives rise to multiple tumours in rats. Radiation alone, with suppression of TSH produces no tumours, TSH-induced growth alone causes a low level of tumorigenesis. Cell proliferation in this model is therefore critical. Epimutation as well as mutation is important. Rodent and human thyroid tumours show a clear stepwise progression, associated with both morphological and oncogene changes. In experimental animals the finding that monoclonal adenomas and carcinomas induced in the presence of long-term high TSH retain TSH dependency suggests that the step in the tumour progression requiring the development of TSH independent growth is bypassed, explaining the frequency of tumour development in this model. Normal thyroid follicular cell growth is limited, and a genotoxic effect before the growth plateau is more effective in carcinogenesis than a genotoxic effect after a period of growth. These observations will be interpreted in relation to the importance of thyroid tumours in regulatory toxicology and the pathobiology of thyroid tumours in man.

Animals↗
PubMed1991

Reversibility of the malignant phenotype in monoclonal tumours in the mouse.

Longterm goitrogen administration to rodents is well known to result in multiple proliferative lesions of the thyroid. The regression of these lesions on withdrawal of goitrogen has led to their neoplastic nature being questioned, and they have been regarded as 'nodules' rather than as true tumours. We have induced multiple thyroid lesions by the combined use of high dose radiation as a mutagen, together with goitrogen administration to induce prolonged TSH growth stimulation. G6PD histochemistry was used in heterozygous G6PD deficient female mice to show that all the thyroid lesions induced by this regime were monophenotypic, and therefore monoclonal in origin. The great majority of induced tumours were adenomas, a minority were carcinomas. The number of carcinomas observed was significantly lower in a group of animals from which goitrogen was withdrawn for 4 weeks prior to killing, when compared to animals killed while on goitrogen treatment. Both adenomas and carcinomas, including areas of intravascular tumour, showed morphological features of regression on withdrawal of the goitrogen. There are three key cellular changes which must occur in spontaneous thyroid carcinogenesis--escape from a growth limiting mechanism, acquisition of TSH independent growth and acquisition of invasiveness. In the natural selection of mutations or epimutations during carcinogenesis, prolonged high levels of TSH are likely to remove any selective advantage from mutations that lead to TSH independent growth. Tumours induced by a regime including prolonged goitrogen treatment may therefore develop following two rather than three key stages. They will occur with an increased frequency relative to lesions observed in spontaneous carcinogenesis, but will retain TSH dependency. We speculate that several mechanisms may lead to loss of the growth limiting mechanism, including translocation of an oncogene to the region of a TSH induced promoter. Other carcinogenic regimes may also increase the yield of tumours by creating conditions which reduce the number of essential steps required for carcinogenesis, and may involve translocation to a carcinogen inducible promoter.

Animals↗
PubMed2025

Fluctuating DNA methylation tracks cancer evolution at clinical scale.

Cancer development and response to treatment are evolutionary processes1,2, but characterizing evolutionary dynamics at a clinically meaningful scale has remained challenging3. Here we develop a new methodology called EVOFLUx, based on natural DNA methylation barcodes fluctuating over time4, that quantitatively infers evolutionary dynamics using only a bulk tumour methylation profile as input. We apply EVOFLUx to 1,976 well-characterized lymphoid cancer samples spanning a broad spectrum of diseases and show that initial tumour growth rate, malignancy age and epimutation rates vary by orders of magnitude across disease types. We measure that subclonal selection occurs only infrequently within bulk samples and detect occasional examples of multiple independent primary tumours. Clinically, we observe faster initial tumour growth in more aggressive disease subtypes, and that evolutionary histories are strong independent prognostic factors in two series of chronic lymphocytic leukaemia. Using EVOFLUx for phylogenetic analyses of aggressive Richter-transformed chronic lymphocytic leukaemia samples detected that the seed of the transformed clone existed decades before presentation. Orthogonal verification of EVOFLUx inferences is provided using additional genetic data, including long-read nanopore sequencing, and clinical variables. Collectively, we show how widely available, low-cost bulk DNA methylation data precisely measure cancer evolutionary dynamics, and provides new insights into cancer biology and clinical behaviour.

Humans↗
PubMed2024

Transgenerational increases in DNA methylation in Arabidopsis plants defective in active DNA demethylation.

Spontaneous gain or loss of DNA methylation occurs in plant and animal genomes, and DNA methylation changes can lead to meiotically stable epialleles that generate heritable phenotypic diversity. However, it is unclear whether transgenerational epigenetic stability may be regulated by any cellular factors. Here, we examined spontaneously occurring variations in DNA methylation in wild-type and ros1 mutant Arabidopsis plants that were propagated for ten generations from single-seed descent. We found that the ros1 mutant, which is defective in active DNA demethylation, showed an increased transgenerational epimutation rate. The ros1 mutation led to more spontaneously gained methylation than lost methylation at individual cytosines, compared to the wild type which had similar numbers of spontaneously gained and lost methylation cytosines. Consistently, transgenerational differentially methylated regions were also biased toward hypermethylation in the ros1 mutant. Our results reveal a genetic contribution of the ROS1 DNA demethylase to transgenerational epigenetic stability and suggest that ROS1 may have an unexpected surveillance function in preventing transgenerational DNA methylation increases.

Arabidopsis↗
PubMed1991

Genetic and environmental modulations of chromosomal stability: their roles in aging and oncogenesis.

The primary objective of this review is to suggest a major role of cytogenetic pathology in the genesis of both the neoplastic phenotype and the senescent phenotype of aging mammalian organisms. It is hypothesized that allelic variation at a number of genetic loci that have the potential to modulate various types of chromosomal mutation could account, in part, for species-specific variations in maximum life-span potentials and the times of onset of characteristic age-related neoplasms. As a corollary to this proposition, attention is directed to the potential importance of environmental clastogens and aneugens as both oncogenic and "gerontogenic" agents. By way of introduction, a series of definitions of our subject material is given (aging, oncogenesis, proliferative homeostasis, point mutation, chromosomal mutation, epimutation, mutagens, clastogens, aneugens, gerontogens). There follows a defense of the view that there is a tight coupling of abnormalities in proliferative homeostasis (including atrophies, hyperplasias, benign neoplasias and malignant neoplasias) with intrinsic biological aging. This view differs from those of other authors who either: 1) believe that, to qualify as a bona fide component of aging, the phenotype in question (in this case, neoplasia) must be "genetically programmed" or 2) insist that the rate of development of the neoplastic phenotype should parallel species-specific Gompertz kinetics for the survival of the population of organisms. After briefly reviewing the classification of chromosomal lesions, we consider evidence for constitutional genetic determinants of chromosomal stability, oncogenesis, and some other aspects of the senescent phenotype, both with respect to interspecific and intraspecific differences. The discussion will include the recent evidence characterizing a human segmental progeroid syndrome (Werner's syndrome) as a deletor mutator strain. A summary of research on environmental chemical clastogens and aneugens is given, showing both discordances and concordances of such assays with assays for point mutagens. An analysis of the literature indicates that there is no statistical evidence for the positive correlations when substances showing effects only at comparatively high concentrations (greater than 1 mM) are excluded from the analysis. Brief mention is also made of the roles of viral agents and ionizing radiation in the genesis of chromosomal mutations. Finally, some possible pathogenetic mechanisms common to chromosomal mutagenicity, oncogenicity and gerontogenicity are considered, including chemical free radicals (active oxygen species), DNA transposition, DNA amplification, DNA glycation, virally induced cell fusion, posttranslational modifications of centromeric and mitotic spindle proteins, and alterations in the metabolism of telomeric DNA.

Aging↗
PubMed2025

Stochastic epigenetic mutation profiles as biomarkers of clinical activity in juvenile idiopathic arthritis: a multi-omic machine learning approach for gene prioritization.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a rare autoimmune disease arising from a complex interplay between genetic and environmental factors. Epigenetic modifications such as DNA methylation (DNAm) have been described as potential mediators in gene-environment interactions, contributing to immune system dysregulation. Emerging evidence suggests that DNAm profiles also predict therapeutic responses in autoimmune diseases. This study aims to identify epigenetic biomarkers and epigenetic-driven gene expression changes associated with JIA clinical activity. METHODS: We reanalyzed a publicly available dataset of 44 JIA patients, with whole-genome DNAm and gene expression from CD4 + T cells measured at two points: at anti-TNF therapy withdrawal (T0) and eight months later (Tend). At Tend, 30 patients maintained inactive disease (ID) while 14 did not (NO ID). We investigated differences between ID and NO ID patients in the epigenetic mutation load and various epigenetic clocks through linear regression models, and prioritized genomic regions with significantly higher number of epimutations in NO ID patients through machine learning. RESULTS: We found a higher mutation load in NO ID than ID patients, both at T0 and at Tend, with the differences at Tend reaching statistical significance (p = 0.02). In contrast, we found no evidence of association between epigenetic clocks and JIA clinical activity. Using a multi-omic approach, we identified a List of candidate epigenetically-driven differentially expressed genes, 80 up-regulated and 77 down-regulated, in NO ID patients. Finally, comparing our candidate gene list with the Connectivity Map database, we identified new candidate potential therapeutic targets. Key findings were validated in independent datasets: DNAm profiles from CD4 + T cells (56 JIA patients, 57 controls) and transcriptomic data from PBMCs of JIA patients with active or inactive disease, confirming dysregulation of pathways such as TNF-α signaling via NF-kB and TGF-β signaling among others. CONCLUSIONS: We described a significant association of epigenetic mutations with JIA clinical activity, indicating that epigenetic changes might precede clinical symptoms and may serve as biomarkers for early disease monitoring. Further, our results shed light on biomolecular mechanisms of JIA, supporting the development of more effective treatments.

Humans↗