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At least 19 recordsLinked to original sources
PubMed1990

DNA methylation and epigenetic inheritance.

Classical genetics has revealed the mechanisms for the transmission of genes from generation to generation, but the strategy of the genes in unfolding the developmental programme remains obscure. Epigenetics comprises the study of the mechanisms that impart temporal and spatial control on the activities of all those genes required for the development of a complex organism from the zygote to the adult. Epigenetic changes in gene activity can be studied in relation to DNA methylation in cultured mammalian cells and it is also possible to isolate and characterize mutants with altered DNA methylase activity. Although this experimental system is quite far removed from the epigenetic controls acting during development it does provide the means to clarify the rules governing the silencing of genes by specific DNA methylation and their reactivation by demethylation. This in turn will facilitate studies on the control of gene expression in somatic cells of the developing organism or the adult. The general principles of epigenetic mechanisms can be defined. There are extreme contrasts between instability or switches in gene expression, such as those in stem-line cells, and the stable heritability of a specialized pattern of gene activities. In some situations cell lineages are known to be important, whereas in others coordinated changes in groups of cells have been demonstrated. Control of numbers of cell divisions and the size of organisms, or parts of organisms, is also essential. The epigenetic determination of gene expression can be reversed or reprogrammed in the germ line. The extent to which methylation or demethylation of specific DNA sequences can help explain these basic epigenetic mechanisms is briefly reviewed.

Aging↗
PubMed1990

Variation in epigenetic inheritance.

Changing patterns of DNA methylation may underlie differential gene expression in development. Additional sources of variation in allelic methylation may be introduced by parental differences as well as by gamete of origin.

Alleles↗
PubMed2026

Combined effects of urine exposure and cryopreservation on sperm quality: an in vitro study of retrograde ejaculation.

Sperm quality influences fertility and offspring health through both genomic inheritance and epigenetic inheritance. Thus, for use in clinical-assisted reproductive technology (ART), spermatozoa must have optimal genomic and epigenetic structures. In patients with retrograde ejaculation, spermatozoa are usually recovered from urine and then cryopreserved for ART. However, the effects of urine exposure and subsequent freeze-thaw cycles on sperm quality remain unclear. This is particularly true for epigenetic changes and their underlying mechanisms. In this study, we examined how different durations of urine exposure (10 min and 40 min) followed by freeze-thaw cycles affected sperm motility, DNA integrity, and methylation levels of imprinting genes (H19-imprinted maternally expressed transcript [ H19 ], mesoderm-specific transcript [ MEST ], and the transposable element Alu [ Alu ]). As the duration of urine exposure increased, sperm motility (median [interquartile range]) decreased from 48.0% (39.0%-52.5%) to 1.0% (1.0%-5.0%), the DNA fragmentation index (DFI; median [interquartile range]) increased from 12.0% (9.3%-19.9%) to 23.5% (13.9%-33.9%), the MEST methylation level (mean ± standard deviation [s.d.]) increased from 3.8% ± 1.5% to 11.5 ± 1.2%, and the H19 methylation level (mean ± s.d.) decreased from 86.9% ± 0.9% to 82.1% ± 0.5%. The freeze-thaw process further reduced sperm motility, while the DFI and methylation levels of MEST and H19 did not significantly change. The Alu methylation level remained stable. These findings demonstrate that urine exposure affects sperm motility, DNA integrity, and methylation levels of some imprinting genes. These effects intensify over time. In contrast, the freeze-thaw process impacts only sperm motility. In clinical practice, minimizing exposure to urine might improve sperm quality.

Humans↗
PubMed2025

A content analysis of health-related epigenetic information in YouTube videos.

PURPOSE: This study aimed to explore how health-related epigenetic concepts are depicted in YouTube videos, a widely accessed platform for informal science education. As epigenetics becomes increasingly relevant to medical therapeutics, it is essential to understand what information is being disseminated in the public sphere. METHODS: We conducted a content analysis of 296 YouTube videos about epigenetics that were under 10 minutes in length. We transcribed and analyzed the videos using an iteratively developed codebook and then categorized relevant codes as categories. RESULTS: We identified 7 categories: (1) defining epigenetics, (2) causes of epigenetic changes, (3) effects of epigenetic change, (4) epigenetic inheritability, (5) application of epigenetics, (6) personal control, and (7) epigenetic mysticism. Although the content about the molecular epigenetic mechanisms mostly aligned with the latest scientific findings, there were numerous unsubstantiated and exaggerated claims about effects of epigenetics on human health, especially disease outcomes. CONCLUSION: We identified several scientific concepts described on YouTube regarding epigenetics. Our findings also reveal what information about epigenetics is widely shared in the public sphere, helping to identify key misconceptions to address and guiding the development of strategies for accurate scientific communication.

Humans↗
PubMed2026

Recurrent reversible mutations at gaf1 driving metastable TORC1 inhibitor resistance in fission yeast.

Metastable phenotypic inheritance is often attributed to epigenetic mechanisms, but reversible genetic alterations can produce similar instability. Here, we investigated the basis of unstable resistance to TORC1 inhibitor (rapamycin plus caffeine) in Schizosaccharomyces pombe. Six independent, metastable resistant mutants were isolated. Genetic mapping positioned the causal lesion to a single Mendelian locus, which sequencing identified as gaf1, encoding a GATA transcription factor and a key negative regulator of growth downstream of TORC1. In each mutant, distinct loss-of-function mutations (insertions, deletions, or point mutations) were found in gaf1 in the resistant state, and these mutations precisely reverted to the wild-type sequence upon loss of resistance. Restoring the wild-type gaf1 allele abolished resistance, indicating that reversible genetic disruption of gaf1 is both necessary and sufficient for the metastable phenotype. Furthermore, strong resistance in several strains from a genome-wide deletion library was due to secondary, inactivating mutations in gaf1, underscoring its role as a recurrent adaptive target under rapamycin plus caffeine treatment. Mechanistically, gaf1 inactivation established a distinct basal transcriptome and pronounced derepression of translation and metabolic programs upon drug treatment. While rapamycin plus caffeine triggered extensive chromatin remodeling and H3K9 methylation contributed partially to resistance, these epigenetic changes were most consistent with a downstream modifying layer. Our study shows that metastable drug resistance in fission yeast is predominantly associated with recurrent, reversible genetic inactivation of the central transcriptional regulator gaf1, demonstrating how rapidly reversible genetic switches can drive adaptive evolution.IMPORTANCEDistinguishing between genetic and epigenetic inheritance is fundamental to understanding how cells adapt to environmental stress. In the fission yeast Schizosaccharomyces pombe, rapid and reversible drug resistance is often assumed to be driven by epigenetic switches that change gene activity without altering DNA. However, our study reveals that this instability can be caused by physical mutations in a single gene, gaf1, which acts as a genetic toggle. These mutations appear under drug pressure and precisely revert to the original sequence when the drug is removed. We also demonstrate that these spontaneous mutations can contaminate standard laboratory yeast collections, leading to potential misinterpretation of experimental data. These findings broaden our understanding of unstable inheritance and show that DNA sequences can be far more dynamic than previously recognized during rapid evolution and the development of drug resistance.

TORC1 signaling↗
PubMed2026

Handle with care: packaging the oocyte epigenome for the next generation.

During oocyte growth, substantial epigenetic programming occurs to establish a distinctive epigenome including appropriately patterned DNA methylation and histone modifications. Oocyte epigenetic programming must be tightly spatiotemporally regulated to ensure that a wide variety of epigenetic modifiers correctly establish their respective modifications to mediate precise control of gene expression. Furthermore, epigenetic modifications in oocytes include canonical and non-canonical genomic imprints, which are transmitted through meiosis to offspring. Significantly, disruptions in oocyte epigenetic programming can cause aberrant developmental outcomes in the next generation mediated by altered imprinting. Polycomb repressive complex 2 is an important epigenetic modifier that establishes histone 3 lysine 27 trimethylation and non-canonical imprints during mouse oogenesis, which are important for normal offspring development. While it is widely recognised that altered oocyte epigenetic programming can disrupt offspring development, mechanisms controlling maternal epigenetic inheritance remain poorly understood. The possibility remains that non-canonical imprinting exists in humans, although this requires confirmation. This review discusses mouse and human oocyte epigenetic programming including interactions between various epigenetic modifiers and modifications that form the unique oocyte epigenome. Understanding how oocyte epigenetic programming is regulated will be crucial in discerning how changes to the oocyte epigenome can disrupt epigenetic memory and alter developmental outcomes in offspring.

Animals↗
PubMed2024

DNA polymerase delta governs parental histone transfer to DNA replication lagging strand.

Chromatin replication is intricately intertwined with the recycling of parental histones to the newly duplicated DNA strands for faithful genetic and epigenetic inheritance. The transfer of parental histones occurs through two distinct pathways: leading strand deposition, mediated by the DNA polymerase ε subunits Dpb3/Dpb4, and lagging strand deposition, facilitated by the MCM helicase subunit Mcm2. However, the mechanism of the facilitation of Mcm2 transferring parental histones to the lagging strand while moving along the leading strand remains unclear. Here, we show that the deletion of Pol32, a nonessential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3-H4 to the leading strand during replication. Biochemical analyses further demonstrate that Pol32 can bind histone H3-H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3-H4 is disrupted through the mutation of the histone H3-H4 binding domain within Mcm2. Our findings identify the DNA polymerase δ subunit Pol32 as a critical histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.

DNA Polymerase III↗
PubMed1990

Models of a dual inheritance system.

In higher plants, animals and fungi, there are two inheritance systems: the familiar system, depending on DNA sequence, used in transmitting information between sexual generations, and an epigenetic inheritance system, depending on gene activation, responsible for the transmission of states of differentiation during development. Occasionally, epigenetic changes are transmitted in sexual reproduction. A formal model of such a dual inheritance system is presented, and it is shown how the separation between the two systems can sometimes break down. The evolutionary significance of such breakdowns is discussed.

Animals↗
PubMed1991

Influence of genome imprinting on gene expression, phenotypic variations and development.

Genome imprinting confers functional differences on parental chromosomes as a result of the differences in epigenetic inheritance from parental germlines. Repressed and derepressed chromatin structures probably constitute the initial germline-dependent 'imprints'. Any subsequent modifications, such as DNA methylation, will be influenced by these initial epigenetic modifications. Hence, epigenetic modifications of parental alleles probably occur progressively and this will affect their potential for expression. It appears that imprinting of some parental alleles is critical for their dosage, affecting embryonic growth, cell proliferation and differentiation. Genetic studies highlight the influence of subsets of imprinted genes and identify those which are crucial for development. Genomic imprinting also affects some transgene loci and dominant mutations with accompanying variable penetrance and expressivity. The response of transgenes can be influenced by modifier genes whose presence is most readily detected in different inbred backgrounds. The influence of modifier genes can in turn be affected by their parental origin, perhaps partly by the maternally inherited oocyte cytoplasmic factors, as well as by complex interactions between some parental alleles and oocyte cytoplasmic factors. The resulting epigenetic modifications of unlinked loci can result in substantial phenotypic variations.

Animals↗
PubMed1992

The use of quantitative genetics for estimating the non-inherited and inherited contributions to metastasis formation.

The contribution of both non-inherited (stochastic, random, environmental, and other non-inherited influences) and inherited factors (genetic and inherited epigenetic factors) to the variability of spontaneous lung metastasis formation in over 100 metastatic lines from each of three murine tumors was measured. The contribution of inherited and genetic sources of variability to metastasis formation was significantly greater than 0 in all cases, but only in the lines of sarcoma SANH was it the major influence on metastatic variability. In the sarcoma SA4020 and hepatocarcinoma HCA-1 lines, non-inherited factors accounted for the majority of the variation in spontaneous lung metastasis formation. A similar situation was also observed in the variability of the tumors with respect to the diameter doubling time. In conclusion, both non-inherited and genetic/inherited factors significantly influenced the formation of spontaneous metastases in the tumors examined. The significance of this finding for the cloning of metastatic genes is discussed.

Animals↗
PubMed1991

Inheritance of phenotype in mammalian cells: genetic vs. epigenetic mechanisms.

Inherited phenotypic changes in cultured cells, as observed during differentiation and transformation, reflect alterations in gene expression and have both a genetic and epigenetic basis. The causes of specific changes are often difficult to define especially when observing phenomenological end points. Although such observations are an important step in defining the phenotypic changes that endure for multiple generations, it is necessary to analyze cells at the molecular level to characterize the pathways leading to changes in phenotype. Gene expression can be regulated at multiple levels, i.e., DNA structure, gene transcription, and/or posttranscriptional modifications. Four genetic mechanisms (DNA point mutations, deletion, rearrangement, and amplification) and two epigenetic mechanisms (DNA methylation and the preservation of DNA-protein complexes) can account for the majority of enduring changes observed in cultured cells. Genetic alterations in DNA sequence appear to be largely responsible for altered growth regulation associated with transformation, but there is also evidence to suggest that epigenetic mechanisms play a role in transformation. Differentiation of cultured cells is often associated with lack of growth, and has been ascribed in part to epigenetic mechanisms. However, differentiation and transformation are not mutually exclusive but may be regulated by parallel multistep pathways. Analysis of the causes underlying transformation has been complicated by the use of aneuploid cells, but it is clear that the tools for overcoming the ambiguities associated with phenomenological analysis are available.

Animals↗
PubMed1991

Mutations in the HML E silencer of Saccharomyces cerevisiae yield metastable inheritance of transcriptional repression.

Mating-type genes resident in the silent cassette HML at the left arm of chromosome III are repressed by the action of four SIR gene products, mediated independently through two cis-acting sites, termed the E and I silencers. We have found that in the absence of the I silencer, deletion of any one of three distinct elements within E yields partial derepression of the mating-type genes resident at HML, whereas deletion of any two yields full derepression. These elements correspond to a binding site for the abundant DNA-binding protein RAP1, an autonomous replicating sequence (ARS), and an as yet undistinguished region. From detailed deletion analysis of the E site we conclude that the ARS element contributes to silencer function in a capacity distinct from its role as an initiator of DNA replication. In addition, we find that strains deleted for any one of these elements comprise two genetically identical but phenotypically distinct types of cells: Those with HML apparently fully derepressed, and those with HML apparently completely repressed. These results reinforce the notion that epigenetic inheritance is an intrinsic characteristic of silencer action.

Chromosomes, Fungal↗
PubMed2025

Preserving centromere identity: right amounts of CENP-A at the right place and time.

Four decades ago, the discovery of centromere protein-A (CENP-A) marked a pivotal breakthrough in chromosome biology, revealing the epigenetic foundation of centromere identity. CENP-A, a histone H3 variant, directs the formation of the microtubule-binding kinetochore complex, designating the chromosomal site for its assembly and underpins the accurate partitioning of genetic material during cell division. Errors in cell division can give rise to DNA instability and aneuploidy, implicated in human diseases such as cancer. Therefore, discovering the underlying pathways and mechanisms responsible for the formation, regulation and maintenance of the centromere is important to our understanding of genome stability, epigenetic inheritance, and in providing the knowledge to help generate possible treatments and therapeutics. Here, we review various molecular pathways and mechanisms implicated in maintaining centromere identity and highlight some of the key outstanding questions with a focus on the human centromere.

Humans↗
PubMed1975

On the relationship between spontaneous mutation rates in vivo and in vitro.

Recent estimates of spontaneous mutation rates in man, in which previous sources of bias are corrected, indicate that the average is about 3 x 10(-7) per locus per generation, a much lower figure than is generally accepted. Assuming 100 to 1000 cell divisions between each gametic union, this information predicts that cellular mutation rats should be in the order of 10(-9) per locus per generation. Since none of the mutation rates measured in cultured cells are this low (average for seven characters equals 7 x 10(-7)), the size of mutation rates in cultured cells cannot be used to substantiate the claim of epigenetic inheritance. Furthermore, this information suggests that in multicellular organisms the germinal tissue is sequestered from mutagenic insult or subjected to selection against mutational damage so as to keep the genetic load of a species at a tolerable level. Alternatively, cell culture environments may present an extremely abnormal situation to somatic cells, thus elevating the mutation rate.

Cells, Cultured↗
PubMed2026

In vitro reconstitution of chromatin replication recapitulates symmetric histone recycling.

Symmetric histone recycling is vital for maintaining epigenetic inheritance upon eukaryotic DNA replication. Recent genome-wide studies have uncovered key determinants of this process, but how these factors collectively support parental histone transfer remains incompletely understood. Here, we successfully reconstitute histone recycling with 24 purified proteins and analyze the products digested by Micrococcal nuclease with Repli-pore-seq, the newly developed pipeline combining nanopore sequencing and deep-learning-based classification. As a result, we identify histones symmetrically recycled as tetrasomes or hexasomes on nucleosome-favorable sequences. We also observe the discordance of the recycled position between lagging and leading strands on the GC-rich DNA sequences. Moreover, removal of Pol δ, Pol32, Dpb3/4, Ctf4, Csm3/Tof1, or Mrc1 disrupts the balance of histone recycling between the two daughter strands, whereas removal of Ctf4, Csm3/Tof1, or Mrc1 additionally alters the positions at which histones were recycled. Furthermore, addition of the lagging-strand maturation factors Fen1 and Cdc9 enhances histone recycling to the lagging strand. These findings provide critical insights into the molecular players and mechanisms underlying symmetric histone recycling.

Histones↗
PubMed2026

A guide to understanding tumour evolution through the lens of population genetics.

Every cancer carries the history of its own evolution, hidden in its genome. Modern DNA sequencing can catalogue millions of mutations and profile tumours across space and time, but sequencing alone struggles to answer the questions that matter most: when did key adaptations emerge, how strongly were they selected, why do some tumours relapse whereas others do not, and how will the cancer evolve next? The reason is fundamental: sequencing is a snapshot, whereas evolution is a dynamic process. Bridging this gap requires moving beyond descriptive cancer genomics towards quantitative evolutionary inference. In this Review, we argue that population genetics provides the mathematical framework needed to extract evolutionary dynamics from cancer genomes. We show how models of mutation, selection and drift transform allele frequencies from descriptive measurements into quantitative estimates of clonal fitness and evolutionary timings. We discuss how these principles extend to epigenetic inheritance, plasticity and ecological interactions within the tumour ecosystem, and examine the assumptions and limitations for their application to modern sequencing data. By reframing cancer genomes as quantitative records of evolutionary processes rather than catalogues of mutations, researchers have used population genetics to provide a foundation for understanding - and ultimately predicting - the trajectories of cancer evolution.

Journal Article↗
PubMed2026

Inheritance of the epigenetic signature and reduced intermuscular bone phenotype acquired via DNA methylation editing of the runx2 b promoter in zebrafish.

The presence of intermuscular bones (IBs) can directly affect the economic value of aquaculture fish. Although genome editing can create IB-free fish by knocking out key IB-related genes, such as runx2b, the associated DNA sequence alterations raise food safety and health concerns, limiting its breeding applications. In this study, we used CRISPR/dCas9-mediated epigenome-editing technology targeting the runx2 b promoter in zebrafish to alter DNA methylation patterns without changing the DNA sequence. Our results showed that higher runx2 b promoter methylation patterns significantly inhibited eGFP mRNA expression levels in the recombinant plasmid. Using the CRISPR/dCas9-Dnmt7 system to enhance methylation of the zebrafish runx2b promoter, we observed a significant decrease in runx2 b mRNA expression levels in the F0 generation. The IBs in the 11 th-16 th muscle segments of the adult F0 fish were significantly shorter compared with the controls. Inbreeding of fish was used to produce F1 and F2 offspring that retained these high promoter methylation levels, along with persistent runx2b expression suppression and IB development inhibition. Transcriptome sequencing analysis suggested that increasing runx2 b promoter methylation levels may synergistically induce additional epigenetic modifications, potentially affecting the PPAR signaling pathway and FoxO transcription factor regulation, which appears to inhibit osteoblast proliferation and differentiation. Overall, this study demonstrates an innovative application of epigenetic editing technology for aquaculture breeding. By precisely regulating the expression patterns of key genes for economically important traits while preserving genomic DNA integrity, this approach provides a theoretical foundation and technical support for improving fish economic traits.

Animals↗