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Chromatin-based epigenetic memory relies on the accurate distribution of parental histone H3-H4 tetramers to newly replicated DNA strands. Mcm2, a subunit of the replicative helicase, and Dpb3/4, subunits of DNA polymerase ε, govern parental histone H3-H4 deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here, using fission yeast heterochromatin inheritance systems that eliminate interference from initiation pathways, we show that a Mcm2 histone binding mutation severely disrupts heterochromatin inheritance, while mutations in Dpb3/4 cause only moderate defects. Surprisingly, simultaneous mutations of Mcm2 and Dpb3/4 stabilize heterochromatin inheritance. eSPAN (enrichment and sequencing of protein-associated nascent DNA) analyses confirmed the conservation of Mcm2 and Dpb3/4 functions in parental histone H3-H4 segregation, with their combined absence showing a more symmetric distribution of parental histone H3-H4 than either single mutation alone. Furthermore, the FACT histone chaperone regulates parental histone transfer to both strands and collaborates with Mcm2 and Dpb3/4 to maintain parental histone H3-H4 density and faithful heterochromatin inheritance. These results underscore the importance of both symmetric distribution of parental histones and their density at daughter strands for epigenetic inheritance and unveil distinctive properties of parental histone chaperones during DNA replication.

Background: The theory of Condition Dependent Sex predicts that – everything else being equal – less fit individuals would outcross at higher rates compared with fitter ones. Here we used the mixed mating plant Lamium amplexicaule, capable of producing both self-pollinating closed flowers (CL), alongside open flowers (CH) that allow cross pollination to test it. We investigated the effects of abiotic stress – salt solution irrigation – on the flowering patterns of plants and their offspring. We monitored several flowering and vegetative parameters, including the number and distribution of flowers, CH fraction, and plant size. Results: We found that stressed plants show an increased tendency for self-pollination and a deficit in floral and vegetative development. However, when parentally primed, stressed plants show a milder response. Un-stressed offspring of stressed parents show reversed responses and exhibit an increased tendency to outcross, and improve floral and vegetative development. Conclusions: In summary, we found that stress affects the reproduction strategy in the plants that experienced the stress and in subsequent offspring through F2 generation. Our results provide experimental evidence supporting a transgenerational extension to the theories of fitness associate sex and dispersal, where an individual's tendency for sex and dispersal may depend on the stress experienced by its parents. [ABSTRACT FROM AUTHOR]

Abstract Background The theory of Condition Dependent Sex predicts that – everything else being equal – less fit individuals would outcross at higher rates compared with fitter ones. Here we used the mixed mating plant Lamium amplexicaule, capable of producing both self-pollinating closed flowers (CL), alongside open flowers (CH) that allow cross pollination to test it. We investigated the effects of abiotic stress – salt solution irrigation – on the flowering patterns of plants and their offspring. We monitored several flowering and vegetative parameters, including the number and distribution of flowers, CH fraction, and plant size. Results We found that stressed plants show an increased tendency for self-pollination and a deficit in floral and vegetative development. However, when parentally primed, stressed plants show a milder response. Un-stressed offspring of stressed parents show reversed responses and exhibit an increased tendency to outcross, and improve floral and vegetative development. Conclusions In summary, we found that stress affects the reproduction strategy in the plants that experienced the stress and in subsequent offspring through F2 generation. Our results provide experimental evidence supporting a transgenerational extension to the theories of fitness associate sex and dispersal, where an individual’s tendency for sex and dispersal may depend on the stress experienced by its parents.

BACKGROUND: Gene-environment interactions contribute to metabolic disorders such as diabetes and dyslipidemia. In addition to affecting metabolic homeostasis directly, drugs and environmental chemicals can cause persistent alterations in metabolic portfolios across generations in a sex-specific manner. Here, we use inorganic arsenic (iAs) as a prototype drug and chemical to dissect such sex differences. METHODS: After weaning, C57BL/6 WT male mice were treated with 250 ppb iAs in drinking water (iAsF0) or normal water (conF0) for 6 weeks and then bred with 15-week-old, non-exposed females for 3 days in cages with only normal water (without iAs), to generate iAsF1 or conF1 mice, respectively. F0 females and all F1 mice drank normal water without iAs all the time. RESULTS: We find that exposure of male mice to 250 ppb iAs leads to glucose intolerance and insulin resistance in F1 female offspring (iAsF1-F), with almost no change in blood lipid profiles. In contrast, F1 males (iAsF1-M) show lower liver and blood triglyceride levels than non-exposed control, with improved glucose tolerance and insulin sensitivity. The liver of F1 offspring shows sex-specific transcriptomic changes, with hepatocyte-autonomous alternations of metabolic fluxes in line with the sex-specific phenotypes. The iAsF1-F mice show altered levels of circulating estrogen and follicle-stimulating hormone. Ovariectomy or liver-specific knockout of estrogen receptor α/β made F1 females resemble F1 males in their metabolic responses to paternal iAs exposure. CONCLUSIONS: These results demonstrate that disrupted reproductive hormone secretion in alliance with hepatic estrogen signaling accounts for the sex-specific intergenerational effects of paternal iAs exposure, which shed light on the sex disparities in long-term gene-environment interactions.

Currently, a central problem for theoretical biology is the integration of development with genetics and evolutionary theory. Through the late 20th century, biologists held that animals resemble their ancestors strictly because of the transgenerational transmission of DNA. This view effectively wrote development out of evolutionary biology. However, many molecular and developmental biologists now understand that phenotypes – anatomical, physiological, and behavioral traits – are not determined by genes (i.e., DNA segments) alone; instead, they emerge epigenetically from developmental processes involving co-acting genetic factors, environmental factors, molecular epigenetic factors, and other non-genetic factors within organisms' bodies. This insight forces a rethinking of biological inheritance. Perspectives focusing on the dynamics of developmental systems offer a compelling alternative way to think about inheritance, providing a powerful substitute to the reductionistic framework that attributes phenotypic outcomes to genetic instructions set in advance of developmental processes. Rethinking genetics, epigenetics, and inheritance by focusing on the dynamics of developmental systems helps highlight the bidirectional effects of evolutionary and developmental processes on one another, yielding a more integrated understanding of development, inheritance, and evolution. Simultaneously, this approach encourages rejection of genetic determinism, a simplistic perspective that continues to appear in psychological writing, despite its biological implausibility. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate age-related changes in histone variant H3.3 and its role in the aging process of mouse tibialis anterior muscle. H3.3 level significantly increased with age and correlated with H3K27me3 level. Acute exercise successfully upregulated the target gene expression in 8-wk-old mice, whereas no upregulation was noted in 53-wk-old mice. H3K27me3 level was increased at these loci in response to acute exercise in 8-wk-old mice. However, in 53-wk-old mice, H3.3 and H3K27me3 levels were increased at rest and were not affected by acute exercise. Furthermore, forced H3.3 expression in the skeletal muscle of 8-wk-old mice led to a gradual improvement in motor function. The results suggest that age-related H3.3 accumulation induces the formation of repressive chromatin in the mouse tibialis anterior muscle. However, H3.3 accumulation also appears to play a positive role in enhancing skeletal muscle function. Keywords: Aging, Epigenetics, Histone modification, Chromatin immunoprecipitation, Exercise, Author(s): Ryo Masuzawa[sup.1], Hemilce Karina Rosa Flete[sup.1], Junya Shimizu[sup.1] and Fuminori Kawano[sup.1] Background Sarcopenia is an age-related pathogenic condition that is characterized by the progressive loss of skeletal muscle mass [...]

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 e 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. [ABSTRACT FROM AUTHOR]

Reports that mouse sperm gain small RNAs from the epididymosomes secreted by epididymal epithelial cells and that these "foreign" small RNAs act as an epigenetic information carrier mediating the transmission of acquired paternal traits have drawn great attention because the findings suggest that heritable information can flow from soma to germ line, thus invalidating the long-standing Weismann's barrier theory on heritable information flow. Using small RNA sequencing (sRNA-seq), northern blots, sRNA in situ hybridization, and immunofluorescence, we detected substantial changes in the small RNA profile in murine caput epididymal sperm (sperm in the head of the epididymis), and we further determined that the changes resulted from sperm exchanging small RNAs, mainly tsRNAs and rsRNAs, with cytoplasmic droplets rather than the epididymosomes. Moreover, the murine sperm-borne small RNAs were mainly derived from the nuclear small RNAs in late spermatids. Thus, caution is needed regarding sperm gaining foreign small RNAs as an underlying mechanism of epigenetic inheritance.

Background: Susceptibility to schizophrenia is determined by interactions between genes and environment, possibly via epigenetic mechanisms. Schizophrenia has been associated with a restrictive epigenome, and histone deacetylase (HDAC) inhibitors have been postulated as coadjuvant agents to potentiate the efficacy of current antipsychotic drugs. We aimed to evaluate global histone posttranslational modifications (HPTMs) and HDAC expression and activity in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Methods: We used postmortem DLPFC samples of individuals with schizophrenia and controls matched for sex, age, and postmortem interval. Schizophrenia samples were classified into antipsychotic-treated or antipsychotic-free subgroups according to blood toxicology. Expression of HPTMs and HDAC was quantified by Western blot. HDAC activity was measured with a fluorometric assay. Results: H3K9ac, H3K27ac, and H3K4me3 were globally enhanced in the DLPFC of individuals with schizophrenia (+24%- 42%, p < 0.05). HDAC activity (-17%, p < 0.01) and HDAC4 protein expression (-20%, p < 0.05) were downregulated in individuals with schizophrenia. Analyses of antipsychotic-free and antipsychotic-treated subgroups revealed enhanced H3K4me3 and H3K27ac (+24%49%, p < 0.05) and reduced HDAC activity in the antipsychotic-treated, but not in the antipsychotic-free subgroup. Limitations: Special care was taken to control the effect of confounding factors: age, sex, postmortem interval, and storage time. However, replication studies in bigger cohorts might strengthen the association between permissive HPTMs and schizophrenia. Conclusion: We found global HPTM alterations consistent with an aberrantly permissive epigenome in schizophrenia. Further studies to elucidate the significance of enhanced permissive HPTMs in schizophrenia and its association with the mechanism of action of antipsychotic drugs are encouraged., Introduction Epigenetics has emerged as the mechanism to explain how environmental factors may have an impact on schizophrenia pathophisiology. (1,2) Histone posttranslational modifications (HPTMs) and DNA methylation are the most [...]

Many toxic metals are involved in the initiation and progression of DNA damage that can result in the activation of DNA damage response machinery at double--and single-stranded DNA; this response can result in global and gene-specific DNA alteration. The toxicological profiles from the Agency for Toxic Substances and Disease Registry (ATSDR) and several other studies have demonstrated the influence of metal exposure- induced genotoxic endpoints and epigenetic modifications. Our review systematically summarizes accumulating evidence from ATSDR toxicological profiles and the available literature that demonstrate a possible induction of various genotoxic endpoints and metal exposures. We include in this article studies on chromium, arsenic, nickel, lead, mercury, and zinc., Introduction This article compiles information from several of the Agency for Toxic Substances and Disease Registry (ATSDR) toxicological profiles to summarize genotoxic endpoints associated with exposure to metals. Humans are [...]