Heritable changes in chromatin contacts linked to transgenerational obesity [ChIP-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE268954 | GEO | 2025/10/17
REPOSITORIES: GEO
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Project description:Burgeoning evidence demonstrates that responses to environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations1,2. This is controversial because underlying mechanisms remain to be identified. Therefore, understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental unanswered question in biology. Here, we used an established murine model of transgenerational obesity to show that direct or ancestral exposure to the obesogen tributyltin (TBT) elicited persistent changes in topologically associating domains (TADs) in primordial germ cells (PGCs) isolated from embryos of exposed and subsequent unexposed generations. New TAD boundaries were formed within the Ide gene encoding insulin degrading enzyme in the exposed PGCs, then stably maintained in PGCs of the subsequent (unexposed) two generations. Concomitantly, Ide mRNA expression was decreased in livers of male descendants from the exposed dams. These animals were hyperinsulinemic and hyperglycemic, phenocopying Ide-deficient mice that are predisposed to adult-onset obesity. Creation of new TAD boundaries in PGCs, suppression of hepatic Ide mRNA, increased fat mass, hyperinsulinemia and hyperglycemia were male-specific. Our results provide a plausible molecular mechanism underlying transmission of the transgenerational predisposition to obesity caused by gestational exposure to an environmental obesogen. They also provide an entry point for future studies aimed at understanding how environmental exposures alter chromatin structure to influence physiology across multiple generations in mammals.
2025-10-17 | GSE218701 | GEO
Project description:Ancestral environmental exposures to non-mutagenic agents can exert effects in unexposed descendants, adding a layer of complexity to long-standing attempts to clarify the relationships between genotypic and phenotypic variations. Transgenerational inheritance of environmental exposures has significant implications for understanding disease etiology. The environmental obesogen hypothesis proposes that exposure to obesogenic chemicals can lead to increased adiposity, in vivo. Here we show that exposure of F0 mice to the obesogen tributyltin (TBT) throughout pregnancy and lactation predisposes unexposed F4 male descendants to obesity when dietary fat is increased. Analyses of body fat, plasma hormone levels, and visceral white adipose tissue DNA methylome and transcriptome collectively indicate that the TBT-dependent F4 obesity is consistent with a leptin resistant, "thrifty phenotype". We found that ancestral TBT exposure induced global changes in DNA methylation together with altered expression of metabolism-relevant genes when the animals were exposed to dietary challenges. Analysis of chromatin accessibility in sperm revealed significant differences between DMSO and TBT groups when guided by DNA sequence composition, a proxy for higher order chromatin organization. Taken together, these data establish an independent connection between ancestral TBT treatment and altered chromatin accessibility that may reflect changes in higher order chromatin organization transmissible through meiosis and mitosis.
2017-11-10 | GSE105051 | GEO
Project description:Epigenetic mechanisms have been found to play important roles in environmental stress response and regulation. These can, theoretically, be transmitted to future unexposed generations, yet few studies have shown persisting stress-induced transgenerational effects, particularly in invertebrates. Here, we focus on the aquatic microcrustacean Daphnia, a parthenogenetic model species, and its response to salinity stress. Salinity is a serious threat to freshwater ecosystems and a relevant form of environmental perturbation affecting freshwater ecosystems. We exposed one generation of D. magna to high levels of salinity (F0) and found that the exposure provoked specific methylation patterns that were transferred to the three consequent non-exposed generations (F1, F2 and F3). This was the case for the hypomethylation of six protein-coding genes with important roles in the organisms’ response to environmental change: DNA damage repair, cytoskeleton organization and protein synthesis. This suggests that epigenetic changes in Daphnia are particularly targeted to genes involved in coping with general cellular stress responses. Our results highlight that epigenetic marks are affected by environmental stressors and can be transferred to subsequent unexposed generations. Epigenetic marks could therefore prove to be useful indicators of past or historic pollution in this parthenogenetic model system. Furthermore, no life history costs seem to be associated with the maintenance of hypomethylation of across unexposed generations in Daphnia following a single stress exposure.
2018-08-20 | GSE107340 | GEO
Project description:Adaptation to environmental stresses is crucial for survival. Transgenerational epigenetic inheritance allows organisms to respond to irregular conditions, alert their naïve descendants that stresses could still be present, and for distant descendants to eventually return to a basal state after several generations without the stress. However, it is still unclear whether organisms adapt on a transgenerational scale after repeated generational exposures to the same environmental stress. We recently found that C. elegans exposed to hypoxia in the parental (P0) generation: increased longevity in the P0 generation, caused an intergenerational reduction in lipids, and elicited a transgenerational reduction in fertility (P0-F2) that was dependent on small RNAs that were transmitted from parents to their naïve children. Here, we find that exposure of subsequent generations of C. elegans to hypoxia caused a transgenerational adaptation such that C. elegans that had repeated generational exposure to hypoxia failed to display hypoxia induced phenotypes. We show that upon two repeated generational exposures to hypoxia, C. elegans no longer display an increase in lifespan, and after four repeated generational exposures to hypoxia, C. elegans no longer display a decrease in reproduction. Transgenerational adaptation of the reproduction phenotype is dependent on the putative H3K27 trimethytransferase PRC2 complex and we identified critical genes that adapted on a transgenerational timeframe to repeated hypoxia exposure. Our findings reveal that transgenerational adaptation occurs and suggest that H3K27me3 is a critical modification for adapting to repeated generational stresses.
2025-09-19 | GSE255871 | GEO
Project description:Environmental challenges experienced by an organism can have multiple effects at an individual level, with recent work also suggesting these challenges may affect their unexposed offspring. In a time of rapid environmental change, understanding whether environmental challenges experienced by organisms could increase the fitness of future generations to survive these same stressors, is critically needed. Low dissolved oxygen is a common environmental challenge that aquatic organisms encounter, resulting in numerous physiological, phenotypic, and epigenetic changes. In this study, we use zebrafish (Danio rerio) as a model to investigate how paternal hypoxia experience impacts subsequent progeny. Males were exposed to moderate hypoxia (11-13 kPA) for 2 weeks, bred to create an F1 generation, and progeny underwent an acute hypoxia (0-1 kPA) tolerance assay. Using time to loss of equilibrium and loss of equilibrium frequency as measured of hypoxia resistance, we show that paternal exposure to hypoxia endow offspring with a greater tolerance to acute hypoxia, compared to offspring of unexposed males, though there are strong family x treatment effects. In addition to phenotypic alternations, we also investigated changes in gene expression in offspring. We conducted RNA-Seq on whole fry and detected 91 differentially expressed genes, including two hemoglobin genes that are significantly upregulated by more than 4-fold in the offspring of hypoxia exposed males. Moreover, the offspring which maintained equilibrium the longest showed the greatest upregulation in hemoglobin expression. Paternal exposures to physiological challenges are thus able to impact the phenotype and gene expression of their unexposed progeny. We conducted whole genome bisulfite sequencing (WGBS) on the sperm of parental males to assess whether changes in progeny phenotype and gene expression are underpinned by changes in DNA methylation. While we observed coupling of methylation levels in the parental sperm and gene expression in progeny overall, we did not detect differential methylation at any of the differentially expressed genes, suggesting that another epigenetic mechanism is responsible for the observed changes in gene expression. Overall, our findings suggest that a ‘memory’ of past hypoxia exposure is maintained and that this environmentally induced information is transferred to subsequent generations, pre-acclimating progeny to cope with hypoxic conditions.
2022-01-01 | GSE160662 | GEO
Project description:Maternal exposures during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. We investigated whether feeding pregnant rats a high fat (HF) or ethinyl-estradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. Here we show that mammary tumorigenesis is higher in daughters and granddaughters of HF rat dams and in daughters, granddaughters and great-granddaughters of EE2 rat dams. Outcross experiments indicate that increased mammary cancer risk is transmitted to HF granddaughters equally through the female or male germlines, but it is only transmitted to EE2 granddaughters through the female germline. The effects of maternal EE2 exposure on offspring's mammary cancer risk are associated with alternations in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and estrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through non-genetic means We examined the whole genome methylation status of both control and EE2-supplemented diet rats in three consecutive generations
2012-09-20 | E-GEOD-40251 | biostudies-arrayexpress
Project description:Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease.
2014-05-16 | GSE57693 | GEO
Project description:Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. Methylated sperm DNA was isolated from rats ancestrally exposed to plastics (Bip), vinclozolin (Vip), pesticides (Pip), dioxin (Hip), jet fuel (Jip) or control vehicle (Cip). Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. For each treatment, treated samples were paired with control samples and hybridized together on arrays (Bip1/Cip1, Bip2/Cip2, Bip3/Cip3, Vip1/Cip1, etc.), resulting in three arrays per treatment group.
2014-05-16 | E-GEOD-57693 | biostudies-arrayexpress
Project description:The ability of environmental exposures in one generation to elicit phenotypic outcomes in subsequent generations suggests that DNA is not the sole vehicle of biological heredity. Such non-genetic inheritance has been demonstrated in a variety of non-mammalian species but, to date, has remained controversial and inadequately characterised in mammals. Here, we show that early life protein restriction (PR) in mice alters DNA methylation at specific genetic variants of multi-copy ribosomal DNA (rDNA), to produce a linear correlation with the extent of growth restriction induced by PR. These effects are common to soma and germ-line and are concomitant with changes in the relative abundance of the responsive rDNA genetic variant. Intergenerational pedigree analysis reveals that rDNA genetic correlations are abolished between directly exposed males and their unexposed offspring, and epigenetic correlations are gained. To the best of our knowledge, this is the first direct demonstration in mammals of epigenetic dynamics induced by gene-environment interactions. Our work confirms rDNA as an evolutionarily conserved target of nutritional insults and intergenerational effects in flies, yeast, and now mice.
2016-07-08 | GSE72608 | GEO
Project description:The ability of environmental exposures in one generation to elicit phenotypic outcomes in subsequent generations suggests that DNA is not the sole vehicle of biological heredity. Such non-genetic inheritance has been demonstrated in a variety of non-mammalian species but, to date, has remained controversial and inadequately characterised in mammals. Here, we show that early life protein restriction (PR) in mice alters DNA methylation at specific genetic variants of multi-copy ribosomal DNA (rDNA), to produce a linear correlation with the extent of growth restriction induced by PR. These effects are common to soma and germ-line and are concomitant with changes in the relative abundance of the responsive rDNA genetic variant. Intergenerational pedigree analysis reveals that rDNA genetic correlations are abolished between directly exposed males and their unexposed offspring, and epigenetic correlations are gained. To the best of our knowledge, this is the first direct demonstration in mammals of epigenetic dynamics induced by gene-environment interactions. Our work confirms rDNA as an evolutionarily conserved target of nutritional insults and intergenerational effects in flies, yeast, and now mice.
2016-07-08 | GSE72607 | GEO