PubMedPro - 表观遗传学

DNA Damage and Repair in Human Reproductive Cells. García-Rodríguez Anaís,Gosálvez Jaime,Agarwal Ashok,Roy Rosa,Johnston Stephen International journal of molecular sciences The fundamental underlying paradigm of sexual reproduction is the production of male and female gametes of sufficient genetic difference and quality that, following syngamy, they result in embryos with genomic potential to allow for future adaptive change and the ability to respond to selective pressure. The fusion of dissimilar gametes resulting in the formation of a normal and viable embryo is known as anisogamy, and is concomitant with precise structural, physiological, and molecular control of gamete function for species survival. However, along the reproductive life cycle of all organisms, both male and female gametes can be exposed to an array of "stressors" that may adversely affect the composition and biological integrity of their proteins, lipids and nucleic acids, that may consequently compromise their capacity to produce normal embryos. The aim of this review is to highlight gamete genome organization, differences in the chronology of gamete production between the male and female, the inherent DNA protective mechanisms in these reproductive cells, the aetiology of DNA damage in germ cells, and the remarkable DNA repair mechanisms, pre- and post-syngamy, that function to maintain genome integrity. 10.3390/ijms20010031

Early-life environmental effects on birds: epigenetics and microbiome as mechanisms underlying long-lasting phenotypic changes. The Journal of experimental biology Although the long-lasting effects of variation in early-life environment have been well documented across organisms, the underlying causal mechanisms are only recently starting to be unraveled. Yet understanding the underlying mechanisms of long-lasting effects can help us predict how organisms will respond to changing environments. Birds offer a great system in which to study developmental plasticity and its underlying mechanisms owing to the production of large external eggs and variation in developmental trajectories, combined with a long tradition of applied, physiological, ecological and evolutionary research. Epigenetic changes (such as DNA methylation) have been suggested to be a key mechanism mediating long-lasting effects of the early-life environment across taxa. More recently, changes in the early-life gut microbiome have been identified as another potential mediator of developmental plasticity. As a first step in understanding whether these mechanisms contribute to developmental plasticity in birds, this Review summarizes how changes in early-life environment (both prenatal and postnatal) influence epigenetic markers and the gut microbiome. The literature shows how both early-life biotic (such as resources and social environment) and abiotic (thermal environment and various anthropogenic stressors) factors modify epigenetic markers and the gut microbiome in birds, yet data concerning many other environmental factors are limited. The causal links of these modifications to lasting phenotypic changes are still scarce, but changes in the hypothalamic-pituitary-adrenal axis have been identified as one putative pathway. This Review identifies several knowledge gaps, including data on the long-term effects, stability of the molecular changes, and lack of diversity in the systems studied, and provides directions for future research. 10.1242/jeb.246024

Phenotypically plastic responses to environmental variation are more complex than life history theory predicts. Evolution; international journal of organic evolution For insects that exhibit wing polyphenic development, abiotic and biotic signals dictate the adult wing morphology of the insect in an adaptive manner such that in stressful environments the formation of a flight-capable morph is favored and in low-stress environments, a flightless morph is favored. While there is a relatively large amount known about the environmental cues that dictate morph formation in wing polyphenic hemipterans like planthoppers and aphids, whether those cues dictate the same morphs in non-hemipteran (i.e., cricket) wing polyphenic species has not been explicitly investigated. To experimentally test the generality of environmental cue determination of wing polyphenism across taxa with diverse life histories, in this study, we tested the importance of food quantity, parasitic infection, and tactile cues on wing morph determination in the wing polyphenic sand field cricket, Gryllus firmus. Our results also show that certain stress cues, such as severe diet quantity limitation and parasitic infection, actually led to an increase in the production of flightless morph. Based on these findings, our results suggest that physiological and genetic constraints are important to an organism's ability to respond to environmental variation in an adaptive manner beyond simple life history trade-offs. 10.1093/evolut/qpae077

Plasticity and environment-specific relationships between gene expression and fitness in . bioRxiv : the preprint server for biology Phenotypic evolution is shaped by interactions between organisms and their environments. The environment influences how an organism's genotype determines its phenotype and how this phenotype affects its fitness. To better understand this dual role of the environment in the production and selection of phenotypic variation, we empirically determined and compared the genotype-phenotype-fitness relationship for mutant strains of the budding yeast in four environments. Specifically, we measured how mutations in the promoter of the metabolic gene modified its expression level and affected its growth on media with four different carbon sources. In each environment, we observed a clear relationship between expression level and fitness, but this relationship differed among environments. Genetic variants with similar effects on expression in different environments often had different effects on fitness and vice versa. Such environment-specific relationships between phenotype and fitness can shape the evolution of phenotypic plasticity. The set of mutants we examined also allowed us to compare the effects of mutations disrupting binding sites for key transcriptional regulators and the TATA box, which is part of the core promoter sequence. Mutations disrupting the binding sites for the transcription factors had more variable effects on expression among environments than mutations disrupting the TATA box, yet mutations with the most environmentally variable effects on fitness were located in the TATA box. This observation suggests that mutations affecting different molecular mechanisms are likely to contribute unequally to regulatory sequence evolution in changing environments. 10.1101/2024.04.12.589130

Variations of salinity during reproduction and development affect ontogenetic trajectories in a coastal amphibian. Environmental science and pollution research international Although coastal ecosystems are naturally submitted to temporal variations of salinity, salinization has been increasing over time threatening coastal biodiversity. Species that exploit such habitats can thus be exposed to brackish water at different life stages. However, the impacts of variations of salinity on wildlife remain poorly understood. This is particularly true for coastal amphibians, due to the strong dependency of early life stages (embryos and larvae) on aquatic environments. In order to investigate the effect of salinity during egg laying and embryonic and larval development of coastal amphibians, we used a full-factorial design to expose reproductive adults, eggs, and larvae of coastal spined toads (Bufo spinosus) to fresh (0 g.l) or brackish water (4 g.l). At egg laying, we evaluated parental investment in reproduction. During embryonic and larval development, we assessed effects on survival, development, and growth. We highlighted strong effects of environmental salinity on reproduction (reduced egg laying time, marginally reduced egg size, and reduced investment in reproduction). Responses to salinity were highly dependent on the developmental stages of exposure (stronger effects when individuals were exposed during embryonic development). These effects carried over when exposure occurred at egg laying or during embryonic development, highlighting the importance of the environmental conditions during early life on ontogenetic trajectories. We also highlighted partial compensation when individuals were transferred back to freshwater. Whether the magnitude of these responses can allow coastal biodiversity to overcome the observed detrimental effects of salinization remain to be assessed. 10.1007/s11356-024-31886-1

The ecology and evolutionary endocrinology of reproduction in the human female. Vitzthum Virginia J American journal of physical anthropology Human reproductive ecology (HRE) is the study of the mechanisms that link variation in reproductive traits with variation in local habitats. Empirical and theoretical contributions from biological anthropology, physiology, and demography have established the foundation necessary for developing a comprehensive understanding, grounded in life history theory (LHT), of temporal, individual, and populational variation in women's reproductive functioning. LHT posits that natural selection leads to the evolution of mechanisms that tend to allocate resources to the competing demands of growth, reproduction, and survival such that fitness is locally maximized. (That is, among alternative allocation patterns exhibited in a population, those having the highest inclusive fitness will become more common over generational time.) Hence, strategic modulation of reproductive effort is potentially adaptive because investment in a new conception may risk one's own survival, future reproductive opportunities, and/or current offspring survival. The hypothalamic-pituitary-ovarian (HPO) axis is the principal neuroendocrine pathway by which the human female modulates reproductive functioning according to the changing conditions in her habitat. Adjustments of reproductive investment in a potential conception are manifested in temporal and individual variation in ovarian cycle length, ovulation, hormone levels, and the probability of conception. Understanding the extent and causes of adaptive and non-adaptive variation in ovarian functioning is fundamental to ascertaining the proximate and remote determinants of human reproductive patterns. In this review I consider what is known and what still needs to be learned of the ecology of women's reproductive biology, beginning with a discussion of the principal explanatory frameworks in HRE and the biometry of ovarian functioning. Turning next to empirical studies, it is evident that marked variation between cycles, women, and populations is the norm rather than an aberration. Other than woman's age, the determinants of these differences are not well characterized, although developmental conditions, dietary practices, genetic variation, and epigenetic mechanisms have all been hypothesized to play some role. It is also evident that the reproductive functioning of women born and living in arduous conditions is not analogous to that of athletes, dieters, or even the lower end of the "normal range" of HPO functioning in wealthier populations. Contrary to the presumption that humans have low fecundity and an inefficient reproductive system, both theory and present evidence suggest that we may actually have very high fecundity and a reproductive system that has evolved to be flexible, ruthlessly efficient and, most importantly, strategic. 10.1002/ajpa.21195

Epigenetic Mechanisms of Plant Adaptation to Biotic and Abiotic Stresses. Ashapkin Vasily V,Kutueva Lyudmila I,Aleksandrushkina Nadezhda I,Vanyushin Boris F International journal of molecular sciences Unlike animals, plants are immobile and could not actively escape the effects of aggressive environmental factors, such as pathogenic microorganisms, insect pests, parasitic plants, extreme temperatures, drought, and many others. To counteract these unfavorable encounters, plants have evolved very high phenotypic plasticity. In a rapidly changing environment, adaptive phenotypic changes often occur in time frames that are too short for the natural selection of adaptive mutations. Probably, some kind of epigenetic variability underlines environmental adaptation in these cases. Indeed, isogenic plants often have quite variable phenotypes in different habitats. There are examples of successful "invasions" of relatively small and genetically homogenous plant populations into entirely new habitats. The unique capability of quick environmental adaptation appears to be due to a high tendency to transmit epigenetic changes between plant generations. Multiple studies show that epigenetic memory serves as a mechanism of plant adaptation to a rapidly changing environment and, in particular, to aggressive biotic and abiotic stresses. In wild nature, this mechanism underlies, to a very significant extent, plant capability to live in different habitats and endure drastic environmental changes. In agriculture, a deep understanding of this mechanism could serve to elaborate more effective and safe approaches to plant protection. 10.3390/ijms21207457

Parental effects in ecology and evolution: mechanisms, processes and implications. Philosophical transactions of the Royal Society of London. Series B, Biological sciences As is the case with any metaphor, parental effects mean different things to different biologists--from developmental induction of novel phenotypic variation to an evolved adaptation, and from epigenetic transference of essential developmental resources to a stage of inheritance and ecological succession. Such a diversity of perspectives illustrates the composite nature of parental effects that, depending on the stage of their expression and whether they are considered a pattern or a process, combine the elements of developmental induction, homeostasis, natural selection, epigenetic inheritance and historical persistence. Here, we suggest that by emphasizing the complexity of causes and influences in developmental systems and by making explicit the links between development, natural selection and inheritance, the study of parental effects enables deeper understanding of developmental dynamics of life cycles and provides a unique opportunity to explicitly integrate development and evolution. We highlight these perspectives by placing parental effects in a wider evolutionary framework and suggest that far from being only an evolved static outcome of natural selection, a distinct channel of transmission between parents and offspring, or a statistical abstraction, parental effects on development enable evolution by natural selection by reliably transferring developmental resources needed to reconstruct, maintain and modify genetically inherited components of the phenotype. The view of parental effects as an essential and dynamic part of an evolutionary continuum unifies mechanisms behind the origination, modification and historical persistence of organismal form and function, and thus brings us closer to a more realistic understanding of life's complexity and diversity. 10.1098/rstb.2008.0302

The interaction between the environment and embryo development in assisted reproduction. Animal reproduction It can be assumed that the natural processes of selection and developmental condition in the animal provide the best prerequisites for embryogenesis resulting in pregnancy and subsequent birth of a healthy neonate. In contrast, circumventing the natural selection mechanisms and all developmental conditions in a healthy animal harbors the risk of counteracting, preventing or reducing the formation of embryos or substantially restricting their genesis. Considering these facts, it seems to be obvious that assisted reproductive techniques focusing on early embryonic stages serve an expanded and unselected germ cell pool of oocytes and sperm cells, and include the culture of embryos outside their natural habitat during and after fertilization for manipulation and diagnostic purposes, and for storage. A significant influence on the early embryonic development is seen in the extracorporeal culture of bovine embryos (in vitro) or stress on the animal organism (in vivo). The in vitro production per se and metabolic as well as endocrine changes in the natural environment of embryos represent adequate models and serve for a better understanding. The purpose of this review is to give a brief presentation of recent techniques aimed at focusing more on the complex processes in the Fallopian tube to contrast in vivo and in vitro prerequisites and abnormalities in early embryonic development and serve to identify potential new ways to make the use of ARTs more feasible. 10.1590/1984-3143-AR2023-0034

The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis. Current environmental health reports PURPOSE OF REVIEW:The developmental origins of health and disease (DOHaD) hypothesis posits that the perinatal environment can impact fetal and later life health. The placenta is uniquely situated to assess prenatal exposures in the context of DOHaD because it is an essential ephemeral fetal organ that manages the transport of oxygen, nutrients, waste, and endocrine signals between the mother and fetus. The purpose of this review is to summarize recent studies that evaluated the DOHaD hypothesis in human placentas using epigenomics, including DNA methylation and transcriptomic studies of mRNA, lncRNA, and microRNAs. RECENT FINDINGS:Between 2016 and 2021, 28 articles evaluated associations between prenatal exposures and placental epigenomics across broad exposure categories including maternal smoking, psychosocial stressors, chemicals, air pollution, and metals. Sixteen of these studies connected exposures to health outcome such as birth weight, fetal growth, or infant neurobehavior through mediation analysis, identification of shared associations between exposure and outcome, or network analysis. These aspects of infant and childhood health serve as a foundation for future studies that aim to use placental epigenetics to understand relationships between the prenatal environment and perinatal complications (such as preterm birth or fetal growth restriction) or later life childhood health. Placental DNA methylation and RNA expression have been linked to numerous prenatal exposures, such as PM2.5 air pollution, metals, and maternal smoking, as well as infant and childhood health outcomes, including fetal growth and birth weight. Placental epigenomics provides a unique opportunity to expand the DOHaD premise, particularly if research applies novel methodologies such as multi-omics analysis, sequencing of non-coding RNAs, mixtures analysis, and assessment of health outcomes beyond early childhood. 10.1007/s40572-022-00354-8

Epigenetics, oestradiol and hippocampal memory consolidation. Journal of neuroendocrinology Epigenetic alterations of histone proteins and DNA are essential for hippocampal synaptic plasticity and cognitive function, and contribute to the aetiology of psychiatric disorders and neurodegenerative diseases. Hippocampal memory formation depends on histone alterations and DNA methylation, and increasing evidence suggests that the regulation of these epigenetic processes by modulatory factors, such as environmental enrichment, stress and hormones, substantially influences memory function. Recent work from our laboratory suggests that the ability of the sex-steroid hormone 17β-oestradiol (E2 ) to enhance novel object recognition memory consolidation in young adult female mice is dependent on histone H3 acetylation and DNA methylation in the dorsal hippocampus. Our data also suggest that enzymes mediating DNA methylation and histone acetylation work in concert to regulate the effects of E2 on memory consolidation. These findings shed light on the epigenetic mechanisms that influence hormonal modulation of cognitive function, and may have important implications for understanding how hormones influence cognition in adulthood and ageing. The present review provides a brief overview of the literature on epigenetics and memory, describes in detail our findings demonstrating that epigenetic alterations regulate E2 -induced memory enhancement in female mice, and discusses future directions for research on the epigenetic regulation of E2 -induced memory enhancement. 10.1111/jne.12106

Advances in epigenetics link genetics to the environment and disease. Nature Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health. 10.1038/s41586-019-1411-0

Synchronization of cyclic and acyclic embryo recipient mares with donor mares. Oliveira Neto Ivan V,Canisso Igor F,Segabinazzi Lorenzo G,Dell'Aqua Camila P F,Alvarenga Marco A,Papa Frederico O,Dell'Aqua Jose A Animal reproduction science This study compared hormone treatments given to mares during anestrus, spring transition, and different stages of the estrous cycle, by assessing uterine features and pregnancy rates after embryo transfer (ET). Embryo recipient mares (n = 160) were equally arranged as follows: G1-spontaneous ovulation (control), G2-anestrus, G3-spring transition, G4-early estrus, G5-estrus, G6-diestrus, G7-early diestrus treated with a dose of dinoprost, and G8-early diestrus treated with two doses of dinoprost. At treatment initiation (Day-4), G2-7 were given dinoprost and estradiol-17β, thereafter, estradiol-17β was repeated on Days-3,-2, and -1. On Day0, mares received long-acting altrenogest. Then, each mare had one ET performed from Day + 3 to Day + 8 after altrenogest. Immediately before the ET, mares received a boost of altrenogest and had uterine features assessed. Pregnant mares on each of the checks (by 7, 30, 60, and 120d after ET) were maintained on weekly injections of LA-P4 until 120d. G8 received similar management, but dinoprost was repeated on Day-3. G1-G6 and G8 displayed uterine edema and satisfactory pregnancy rates ≥65%. Repeating dinoprost to G8 likely ensured proper luteolysis and response to estrogen as determined by higher uterine edema scores and pregnancy rates than G7 (p < .05). Our results were consistent with previous studies and other successful commercial ET programs (except G7), thus, demonstrating the usefulness of the hormone treatments described herein to synchronize embryo recipient mares with donor mares. Thus, we foresee that other groups may use the strategies described herein for the management of embryo recipient mares. 10.1016/j.anireprosci.2017.12.016

Alterations in epigenetic modifications during oocyte growth in mice. Kageyama Shun-ichiro,Liu Honglin,Kaneko Naoto,Ooga Masatoshi,Nagata Masao,Aoki Fugaku Reproduction (Cambridge, England) During oocyte growth, chromatin structure is altered globally and gene expression is silenced. To investigate the involvement of epigenetic modifications in the regulation of these phenomena, changes in global DNA methylation and in various histone modifications, i.e. acetylation of H3K9, H3K18, H4K5, and H4K12, and methylation of H3K4 and H3K9, were examined during the growth of mouse oocytes. Immunocytochemical analysis revealed that the signal intensities of all these modifications increased during growth and that fully grown, germinal vesicle (GV)-stage oocytes showed the most modifications. Since acetylation of most of the lysine residues on histones and methylation of H3K4 are associated with active gene expression, the increased levels of these modifications do not seem to be associated with gene silencing in GV-stage oocytes. Given that there are two types of GV-stage oocytes with different chromatin configurations and transcriptional activities, the epigenetic modification statuses of these two types were compared. The levels of all the epigenetic modifications examined were higher in the SN(surrounded nucleolus)-type oocytes, in which highly condensed chromatin is concentrated in the area around the nucleolus and gene expression is silenced than in the NSN(not surrounded nucleolus)-type oocytes, in which less-condensed chromatin does not surround the nucleolus and gene expression is active. In addition, the expression levels of various enzymes that catalyze histone modifications were shown by RT-PCR to increase with oocyte growth. Taken together, the results show that all of the epigenetic modifications increased in a concerted manner during oocyte growth, and suggest that these increases are not associated with gene expression. 10.1530/REP-06-0025

DNA methylation, an epigenetic mode of gene expression regulation in reproductive science. Calicchio Rosamaria,Doridot Ludivine,Miralles Francisco,Méhats Céline,Vaiman Daniel Current pharmaceutical design DNA methylation is an important part of the epigenetic code governing gene expression. In human reproductive diseases, recent studies have shown the existence of deviations from the normal methylation profile at various genome loci. In this review, this type of epigenetic alterations is explored in pathological spermatogenesis, ovarian diseases, placental syndromes, such as preeclampsia and Intra- Uterine Growth Restriction, uterine diseases such as endometriosis, and putative pathophysiological effects of Assisted Reproductive Technologies. We review the notion of epigenetics, the technical methods available to analyze methylation, and the known associations between reproductive diseases and DNA methylation, focusing on human pathologies and on animal models when available. We show that imprinted genes control regions (ICRs) are a prominent and frequent target of methylation anomalies in reproductive disorders, but such alterations also affect non-imprinted genes. The mechanistic aspects of gene regulation in response to methylation anomalies are also discussed in this review when they have been investigated.

Epigenetic Regulation and Risk Factors During the Development of Human Gametes and Early Embryos. Wang Yang,Liu Qiang,Tang Fuchou,Yan Liying,Qiao Jie Annual review of genomics and human genetics Drastic epigenetic reprogramming occurs during human gametogenesis and early embryo development. Advances in low-input and single-cell epigenetic techniques have provided powerful tools to dissect the genome-wide dynamics of different epigenetic molecular layers in these processes. In this review, we focus mainly on the most recent progress in understanding the dynamics of DNA methylation, chromatin accessibility, and histone modifications in human gametogenesis and early embryo development. Deficiencies in remodeling of the epigenomes can cause severe developmental defects, infertility, and long-term health issues in offspring. Aspects of the external environment, including assisted reproductive technology procedures, parental diets, and unhealthy parental habits, may disturb the epigenetic reprogramming processes and lead to an aberrant epigenome in the offspring. Here, we review the current knowledge of the potential risk factors of aberrant epigenomes in humans. 10.1146/annurev-genom-083118-015143

Superovulation alters global DNA methylation in early mouse embryo development. Yu Bo,Smith Thomas H,Battle Stephanie L,Ferrell Shannon,Hawkins R David Epigenetics Assisted reproductive technologies are known to alter the developmental environment of gametes and early embryos during the most dynamic period of establishing the epigenome. This may result in the introduction of errors during active DNA methylation reprogramming. Controlled ovarian hyperstimulation, or superovulation, is a ubiquitously used intervention which has been demonstrated to alter the methylation of certain imprinted genes. The objective of this study was to investigate whether ovarian hyperstimulation results in genome-wide DNA methylation changes in mouse early embryos. Ovarian hyperstimulation was induced by treating mice with either low doses (5 IU) or high doses (10 IU) of PMSG and hCG. Natural mating (NM) control mice received no treatment. Zygotes and 8-cell embryos were collected from each group and DNA methylomes were generated by whole-genome bisulfite sequencing. In the NM group, mean CpG methylation levels slightly decreased from zygote to 8-cell stage, whereas a large decrease in mean CpG methylation level was observed in both superovulated groups. A separate analysis of the mean CpG methylation levels within each developmental stage confirmed that significant genome-wide erasure of CpG methylation from the zygote to 8-cell stage only occurred in the superovulation groups. Our results suggest that superovulation alters the genome-wide DNA methylation erasure process in mouse early pre-implantation embryos. It is not clear whether these changes are transient or persistent. Further studies are ongoing to investigate the impact of ovarian hyperstimulation on DNA methylation re-establishment in later stages of embryo development. 10.1080/15592294.2019.1615353

Conservation of DNA Methylation Programming Between Mouse and Human Gametes and Preimplantation Embryos. White Carlee R,MacDonald William A,Mann Mellissa R W Biology of reproduction In mice, assisted reproductive technologies (ARTs) applied during gametogenesis and preimplantation development can result in disruption of genomic imprinting. In humans, these technologies and/or subfertility have been linked to perturbations in genomic imprinting. To understand how ARTs and infertility affect DNA methylation, it is important to understand DNA methylation dynamics and the role of regulatory factors at these critical stages. Recent genome studies performed using mouse and human gametes and preimplantation embryos have shed light onto these processes. Here, we comprehensively review the current state of knowledge regarding global and imprinted DNA methylation programming in the mouse and human. Available data highlight striking similarities in mouse and human DNA methylation dynamics during gamete and preimplantation development. Just as fascinating, these studies have revealed sex-, gene-, and allele-specific differences in DNA methylation programming, warranting future investigation to untangle the complex regulation of DNA methylation dynamics during gamete and preimplantation development. 10.1095/biolreprod.116.140319

Epigenetic pre-patterning and dynamics during initial stages of mammalian preimplantation development. Rasmussen Theodore P,Corry Gareth N Journal of cellular physiology Mammals, like all multicellular organisms, develop from a single cell--the totipotent zygote. During preimplantation development and subsequent development in utero, over 200 distinct cell types are established and integrated into the organ systems and tissues of the developing organism. Much of the field of mammalian developmental biology is devoted to investigation of mechanisms that govern the formation of complete organs and tissues. In contrast to later development, which consumes the vast majority of time associated with development in utero, preimplantation development and germ layer specification occur rapidly. Yet knowledge is limited regarding the regulatory mechanisms that specify the transient, but pluripotent, cellular lineages that form during the initial stages of mammalian development. Gametogenesis and preimplantation development are marked by dramatic and pervasive epigenetic changes rooted in chromatin dynamics. The fundamental mechanisms that specify subsequent cellular lineages of the conceptus are only now becoming understood, and tend to rely relatively heavily upon broad epigenetic mechanisms in addition to master transcription factors. This review considers epigenetic regulation in the very earliest stages of preimplantation development. In addition, recent advances which indicate that some epigenetic coding is imposed during gametogenesis and maintained during preimplantation development are considered. 10.1002/jcp.22293

Epigenetic dynamics during preimplantation development. Marcho Chelsea,Cui Wei,Mager Jesse Reproduction (Cambridge, England) Successful mammalian development requires descendants of single-cell zygotes to differentiate into diverse cell types even though they contain the same genetic material. Preimplantation dynamics are first driven by the necessity of reprogramming haploid parental epigenomes to reach a totipotent state. This process requires extensive erasure of epigenetic marks shortly after fertilization. During the few short days after formation of the zygote, epigenetic programs are established and are essential for the first lineage decisions and differentiation. Here we review the current understanding of DNA methylation and histone modification dynamics responsible for these early changes during mammalian preimplantation development. In particular, we highlight insights that have been gained through next-generation sequencing technologies comparing human embryos to other models as well as the recent discoveries of active DNA demethylation mechanisms at play during preimplantation. 10.1530/REP-15-0180

DNA Methylation and Histone Modification Are the Possible Regulators of Preimplantation Blastocyst Activation in Mice. Reproductive sciences (Thousand Oaks, Calif.) Under ovarian hormone control, dormant blastocysts obtain implantation capacity (known as blastocyst activation) through their global gene expression. After the activated blastocysts communicate with the receptive uterus, the implantation-competent blastocysts start the implantation. Although dormant and activated blastocysts have different gene expression levels, the regulatory mechanisms underlying these transcriptions remain unclear. Hence, this study aimed to analyze epigenetic marks in dormant and activated blastocysts. In mice, blastocyst dormancy is artificially induced by daily progesterone injection without estrogen supplementation after peri-implantation ovariectomy; when estrogen is administered concomitantly, blastocyst activation and implantation occur. These phenomena demonstrate a mouse model of delayed implantation. We collected dormant and activated blastocysts from a delayed implantation mouse model. RNA-seq, methylated DNA immunoprecipitation (MeDIP)-seq, and chromatin immunoprecipitation (ChIP)-seq for H3K4 me3 and H3K27 me3 were performed using dormant and activated blastocysts. Cell cycle-related transcripts were affected during blastocyst activation. DNA methylations were accumulated in downregulated genes in the activated blastocysts. Histone H3 trimethylations were globally altered between the dormant and activated blastocysts. Dormant and activated blastocysts have unique methylation patterns on DNA and histone H3, with high correlation to gene expression. DNA methylation and histone modification can regulate preimplantation blastocyst activation. 10.1007/s43032-022-00988-x

PERSPECTIVE: Cryopreservation of Human Oocytes and the 'Carryover' Effect on Early Embryo Development. Jia Q P,Sun W Q Cryo letters Worldwide women are increasingly facing the issue of delayed child-bearing and fertility decline. Oocyte cryopreservation provides an option for fertility preservation, especially for women with diseases and other special needs to conceive babies later. In this review we examine the effect of oocyte cryopreservation on early development of human embryos. Databases (Medline, PubMed and Web of Science) were searched for relevant clinical studies published between 1999 and 2020. A total of 27 studies on oocyte cryopreservation and embryo development were identified, and data in those studies are retrieved for meta-analysis on the outcomes of oocyte survival, fertilization and early embryo development. In comparison to the slow freezing technique, vitrification yields significantly better oocyte survival (84.7% ± 0.6% vs 58.0% ± 0.5%), and subsequently higher rates of fertilization (65.5% ± 0.9% vs 40.0% ± 0.6%), cleavage (58.8% ± 0.9% vs 34.6% ± 0.8%), as well as embryo implantation (5.9% ± 0.3% vs 2.9% ± 0.2%). This analysis reveals a negative 'carryover' effect of oocyte cryopreservation on early development of embryos after oocyte fertilization (i.e., cleavage and implantation). This 'carryover' effect is greater for slowly-frozen oocytes than for vitrified oocytes, and may represent subtle functional or molecular alterations that are not severe enough to affect cell survival and fertilization, but sufficient to impair later development. The nature of the 'carryover' effect is unknown. Hypothermia, membrane ion channels, bioenergy metabolism and epigenetic modifications are likely involved. In conclusion, oocyte cryopreservation can negatively affect early development of human embryos. Future studies should go beyond oocyte survival and look further into the effects on epigenetic changes.

Epigenetic disorders and altered gene expression after use of Assisted Reproductive Technologies in domestic cattle. Urrego Rodrigo,Rodriguez-Osorio Nélida,Niemann Heiner Epigenetics The use of Assisted Reproductive Technologies (ARTs) in modern cattle breeding is an important tool for improving the production of dairy and beef cattle. A frequently employed ART in the cattle industry is in vitro production of embryos. However, bovine in vitro produced embryos differ greatly from their in vivo produced counterparts in many facets, including developmental competence. The lower developmental capacity of these embryos could be due to the stress to which the gametes and/or embryos are exposed during in vitro embryo production, specifically ovarian hormonal stimulation, follicular aspiration, oocyte in vitro maturation in hormone supplemented medium, sperm handling, gamete cryopreservation, and culture of embryos. The negative effects of some ARTs on embryo development could, at least partially, be explained by disruption of the physiological epigenetic profile of the gametes and/or embryos. Here, we review the current literature with regard to the putative link between ARTs used in bovine reproduction and epigenetic disorders and changes in the expression profile of embryonic genes. Information on the relationship between reproductive biotechnologies and epigenetic disorders and aberrant gene expression in bovine embryos is limited and novel approaches are needed to explore ways in which ARTs can be improved to avoid epigenetic disorders. 10.4161/epi.28711

Embryonic imprinting perturbations do not originate from superovulation-induced defects in DNA methylation acquisition. Denomme Michelle M,Zhang Liyue,Mann Mellissa R W Fertility and sterility OBJECTIVE:To investigate whether superovulation disrupts maternal imprint acquisition in oocytes. DESIGN:Animal model. SETTING:Academic institute. ANIMAL(S):Spontaneously ovulated and superovulated mice. INTERVENTION(S):Low and high hormone dosage treatments were administered to females, and ovulated metaphase II oocytes were collected. MAIN OUTCOME MEASURE(S):Imprinted DNA methylation was analyzed at Snrpn, Kcnq1ot1, Peg3, and H19 in individual oocytes. RESULT(S):Examination of 125 individual oocytes derived from females subjected to low and high hormone treatments revealed normal imprinted methylation patterns that were comparable to oocytes derived from spontaneously ovulated females. CONCLUSION(S):Maternal imprint acquisition was not affected by superovulation. Given its aberrant effects during preimplantation development, superovulation must instead disrupt maternal-effect gene products that are required after fertilization for imprint maintenance. These results eliminate imprint acquisition per se as the initial stage of imprint loss and point to the importance of analyses on early embryos after procedures involving oocyte manipulation. 10.1016/j.fertnstert.2011.06.055

Genome-wide assessment of DNA methylation in mouse oocytes reveals effects associated with in vitro growth, superovulation, and sexual maturity. Saenz-de-Juano Maria Desemparats,Ivanova Elena,Billooye Katy,Herta Anamaria-Cristina,Smitz Johan,Kelsey Gavin,Anckaert Ellen Clinical epigenetics BACKGROUND:In vitro follicle culture (IFC), as applied in the mouse system, allows the growth and maturation of a large number of immature preantral follicles to become mature and competent oocytes. In the human oncofertility clinic, there is increasing interest in developing this technique as an alternative to ovarian cortical tissue transplantation and to preserve the fertility of prepubertal cancer patients. However, the effect of IFC and hormonal stimulation on DNA methylation in the oocyte is not fully known, and there is legitimate concern over epigenetic abnormalities that could be induced by procedures applied during assisted reproductive technology (ART). RESULTS:In this study, we present the first genome-wide analysis of DNA methylation in MII oocytes obtained after natural ovulation, after IFC and after superovulation. We also performed a comparison between prepubertal and adult hormonally stimulated oocytes. Globally, the distinctive methylation landscape of oocytes, comprising alternating hyper- and hypomethylated domains, is preserved irrespective of the procedure. The conservation of methylation extends to the germline differential methylated regions (DMRs) of imprinted genes, necessary for their monoallelic expression in the embryo. However, we do detect specific, consistent, and coherent differences in DNA methylation in IFC oocytes, and between oocytes obtained after superovulation from prepubertal compared with sexually mature females. Several methylation differences span entire transcription units. Among these, we found alterations in Tcf4, Sox5, Zfp521, and other genes related to nervous system development. CONCLUSIONS:Our observations show that IFC is associated with altered methylation at specific set of loci. DNA methylation of superovulated prepubertal oocytes differs from that of superovulated adult oocytes, whereas oocytes from superovulated adult females differ very little from naturally ovulated oocytes. Importantly, we show that regions other than imprinted gDMRs are susceptible to methylation changes associated with superovulation, IFC, and/or sexual immaturity in mouse oocytes. Our results provide an important reference for the use of in vitro growth and maturation of oocytes, particularly from prepubertal females, in assisted reproductive treatments or fertility preservation. 10.1186/s13148-019-0794-y

The effect of progesterone and exogenous gonadotropin on preimplantation mouse embryo development and implantation. Ghaemi Soraya Rasi,Salehnia Mojdeh,Valojerdi Mojtaba Rezazadeh Experimental animals The aim of this study was to evaluate the effects of progesterone and ovarian stimulation on the development and implantation rate of mouse embryos. Two-cell embryos were collected from superovulated mice and cultured in the presence of different concentrations of progesterone (0, 5, 10 and 20 ng/ml). Also other mice were rendered pregnant in unstimulated, unstimulated progesterone-injected, superovulated and superovulated progesterone-injected groups to collect the blastocysts. The number of blastocysts and implantation sites were recorded on the 4th and 7th day of pregnancy, respectively. The diameter and cell number of blastocysts were analyzed in the in vitro and in vivo groups. After 120 h culture, the percentage of hatched blastocyst embryos in control and 5, 10 and 20 ng/ml progesterone-injected groups were 63.9%, 64.2%, 64.2% and 75.6% respectively. There were significant differences between the developmental rates of embryos in the presence of 20 ng/ml progesterone and the control and other concentrations of progesterone-injected groups (P< or =0.001). The in vivo blastocyst survival rate (97.68%) and implantation rate (92.06%) in the unstimulated and progesterone-injected groups were higher than in the other groups. Blastocyst cell numbers in the superovulated (128.62 +/- 1.30) and superovulated progesterone-injected groups (126.88 +/- 1.60) were significantly different from the control (P<0.001). The progesterone injection without ovarian induction improved the embryo survival and implantation rates, but after superovulation it did not ameliorate the negative effects of superovulation on the implantation rate. 10.1538/expanim.57.27

Genetic and epigenetic regulators of pluripotency. Surani M Azim,Hayashi Katsuhiko,Hajkova Petra Cell Genetic and epigenetic mechanisms regulate the transition from the totipotent zygote to pluripotent primitive ectoderm cells in the inner cell mass of mouse blastocysts. These pluripotent cells can be propagated indefinitely in vitro, underpinned by a unique epigenetic state. Following implantation of the blastocyst, diverse epigenetic modifiers control differentiation of pluripotent epiblast cells into somatic cells, while specification of germ cells requires repression of the somatic program. Regenerating totipotency during development of germ cells entails re-expression of pluripotency-specific genes and extensive erasure of epigenetic modifications. Increasing knowledge of key underlying mechanisms heightens prospects for creating pluripotent cells directly from adult somatic cells. 10.1016/j.cell.2007.02.010

Transcriptional and epigenetic mechanisms of cellular reprogramming to induced pluripotency. van den Hurk Mark,Kenis Gunter,Bardy Cedric,van den Hove Daniel L,Gage Fred H,Steinbusch Harry W,Rutten Bart P Epigenomics Enforced ectopic expression of a cocktail of pluripotency-associated genes such as Oct4, Sox2, Klf4 and c-Myc can reprogram somatic cells into induced pluripotent stem cells (iPSCs). The remarkable proliferation ability of iPSCs and their aptitude to redifferentiate into any cell lineage makes these cells a promising tool for generating a variety of human tissue in vitro. Yet, pluripotency induction is an inefficient process, as cells undergoing reprogramming need to overcome developmentally imposed epigenetic barriers. Recent work has shed new light on the molecular mechanisms that drive the reprogramming of somatic cells to iPSCs. Here, we present current knowledge on the transcriptional and epigenetic regulation of pluripotency induction and discuss how variability in epigenetic states impacts iPSCs' inherent biological properties. 10.2217/epi-2016-0032

Epigenetic regulation of pluripotency and differentiation. Boland Michael J,Nazor Kristopher L,Loring Jeanne F Circulation research The precise, temporal order of gene expression during development is critical to ensure proper lineage commitment, cell fate determination, and ultimately, organogenesis. Epigenetic regulation of chromatin structure is fundamental to the activation or repression of genes during embryonic development. In recent years, there has been an explosion of research relating to various modes of epigenetic regulation, such as DNA methylation, post-translational histone tail modifications, noncoding RNA control of chromatin structure, and nucleosome remodeling. Technological advances in genome-wide epigenetic profiling and pluripotent stem cell differentiation have been primary drivers for elucidating the epigenetic control of cellular identity during development and nuclear reprogramming. Not only do epigenetic mechanisms regulate transcriptional states in a cell-type-specific manner but also they establish higher order genomic topology and nuclear architecture. Here, we review the epigenetic control of pluripotency and changes associated with pluripotent stem cell differentiation. We focus on DNA methylation, DNA demethylation, and common histone tail modifications. Finally, we briefly discuss epigenetic heterogeneity among pluripotent stem cell lines and the influence of epigenetic patterns on genome topology. 10.1161/CIRCRESAHA.115.301517

DNA methylation dynamics during the mammalian life cycle. Hackett Jamie A,Surani M Azim Philosophical transactions of the Royal Society of London. Series B, Biological sciences DNA methylation is dynamically remodelled during the mammalian life cycle through distinct phases of reprogramming and de novo methylation. These events enable the acquisition of cellular potential followed by the maintenance of lineage-restricted cell identity, respectively, a process that defines the life cycle through successive generations. DNA methylation contributes to the epigenetic regulation of many key developmental processes including genomic imprinting, X-inactivation, genome stability and gene regulation. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within distinct genomic contexts, such as at promoters, exons or imprinted control regions. Additionally, there is a better understanding of the mechanistic basis of DNA demethylation during epigenetic reprogramming in primordial germ cells and during pre-implantation development. Here, we discuss our current understanding of the developmental roles and dynamics of this key epigenetic system. 10.1098/rstb.2011.0328

Dynamics and function of DNA methylation in plants. Zhang Huiming,Lang Zhaobo,Zhu Jian-Kang Nature reviews. Molecular cell biology DNA methylation is a conserved epigenetic modification that is important for gene regulation and genome stability. Aberrant patterns of DNA methylation can lead to plant developmental abnormalities. A specific DNA methylation state is an outcome of dynamic regulation by de novo methylation, maintenance of methylation and active demethylation, which are catalysed by various enzymes that are targeted by distinct regulatory pathways. In this Review, we discuss DNA methylation in plants, including methylating and demethylating enzymes and regulatory factors, and the coordination of methylation and demethylation activities by a so-called methylstat mechanism; the functions of DNA methylation in regulating transposon silencing, gene expression and chromosome interactions; the roles of DNA methylation in plant development; and the involvement of DNA methylation in plant responses to biotic and abiotic stress conditions. 10.1038/s41580-018-0016-z

Methylation deficiency disrupts biological rhythms from bacteria to humans. Fustin Jean-Michel,Ye Shiqi,Rakers Christin,Kaneko Kensuke,Fukumoto Kazuki,Yamano Mayu,Versteven Marijke,Grünewald Ellen,Cargill Samantha J,Tamai T Katherine,Xu Yao,Jabbur Maria Luísa,Kojima Rika,Lamberti Melisa L,Yoshioka-Kobayashi Kumiko,Whitmore David,Tammam Stephanie,Howell P Lynne,Kageyama Ryoichiro,Matsuo Takuya,Stanewsky Ralf,Golombek Diego A,Johnson Carl Hirschie,Kakeya Hideaki,van Ooijen Gerben,Okamura Hitoshi Communications biology The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. We have previously shown that methyl cycle inhibition in mammals strongly affects circadian rhythms. Since the methyl cycle and circadian clocks have evolved early during evolution and operate in organisms across the tree of life, we sought to determine whether the link between the two is also conserved. Here, we show that methyl cycle inhibition affects biological rhythms in species ranging from unicellular algae to humans, separated by more than 1 billion years of evolution. In contrast, the cyanobacterial clock is resistant to methyl cycle inhibition, although we demonstrate that methylations themselves regulate circadian rhythms in this organism. Mammalian cells with a rewired bacteria-like methyl cycle are protected, like cyanobacteria, from methyl cycle inhibition, providing interesting new possibilities for the treatment of methylation deficiencies. 10.1038/s42003-020-0942-0

Effects of temperature and relative humidity on DNA methylation. Bind Marie-Abele,Zanobetti Antonella,Gasparrini Antonio,Peters Annette,Coull Brent,Baccarelli Andrea,Tarantini Letizia,Koutrakis Petros,Vokonas Pantel,Schwartz Joel Epidemiology (Cambridge, Mass.) BACKGROUND:Previous studies have found relationships between DNA methylation and various environmental contaminant exposures. Associations with weather have not been examined. Because temperature and humidity are related to mortality even on non-extreme days, we hypothesized that temperature and relative humidity may affect methylation. METHODS:We repeatedly measured methylation on long interspersed nuclear elements (LINE-1), Alu, and 9 candidate genes in blood samples from 777 elderly men participating in the Normative Aging Study (1999-2009). We assessed whether ambient temperature and relative humidity are related to methylation on LINE-1 and Alu, as well as on genes controlling coagulation, inflammation, cortisol, DNA repair, and metabolic pathway. We examined intermediate-term associations of temperature, relative humidity, and their interaction with methylation, using distributed lag models. RESULTS:Temperature or relative humidity levels were associated with methylation on tissue factor (F3), intercellular adhesion molecule 1 (ICAM-1), toll-like receptor 2 (TRL-2), carnitine O-acetyltransferase (CRAT), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and glucocorticoid receptor, LINE-1, and Alu. For instance, a 5°C increase in 3-week average temperature in ICAM-1 methylation was associated with a 9% increase (95% confidence interval: 3% to 15%), whereas a 10% increase in 3-week average relative humidity was associated with a 5% decrease (-8% to -1%). The relative humidity association with ICAM-1 methylation was stronger on hot days than mild days. CONCLUSIONS:DNA methylation in blood cells may reflect biological effects of temperature and relative humidity. Temperature and relative humidity may also interact to produce stronger effects. 10.1097/EDE.0000000000000120

Genetic and Epigenetic Understanding of the Seasonal Timing of Flowering. He Yuehui,Chen Tao,Zeng Xiaolin Plant communications The developmental transition to flowering in many plants is timed by changing seasons, which enables plants to flower at a season that is favorable for seed production. Many plants grown at high latitudes perceive the seasonal cues of changing day length and/or winter cold (prolonged cold exposure), to regulate the expression of flowering-regulatory genes through the photoperiod pathway and/or vernalization pathway, and thus align flowering with a particular season. Recent studies in the model flowering plant have revealed that diverse transcription factors engage various chromatin modifiers to regulate several key flowering-regulatory genes including () and () in response to seasonal signals. Here, we summarize the current understanding of molecular and chromatin-regulatory or epigenetic mechanisms underlying the vernalization response and photoperiodic control of flowering in . Moreover, the conservation and divergence of regulatory mechanisms for seasonal flowering in crops and other plants are briefly discussed. 10.1016/j.xplc.2019.100008

Perfect timing: epigenetic regulation of the circadian clock. Ripperger Jürgen A,Merrow Martha FEBS letters In mammals, higher order chromatin structures are critical for downsizing the genome (packaging) so that the nucleus can be small. The adjustable density of chromatin also regulates gene expression, thus this post-genetic molecular mechanism is one of the routes by which phenotype is shaped. Phenotypes that arise without a concomitant mutation of the underlying genome are termed epigenetic phenomena. Here we discuss epigenetic phenomena from histone and DNA modification as it pertains to the dynamic regulatory processes of the circadian clock. Epigenetic phenomena certainly explain some regulatory aspects of the mammalian circadian oscillator. 10.1016/j.febslet.2011.04.047

DNA methylation dynamics during early plant life. Bouyer Daniel,Kramdi Amira,Kassam Mohamed,Heese Maren,Schnittger Arp,Roudier François,Colot Vincent Genome biology BACKGROUND:Cytosine methylation is crucial for gene regulation and silencing of transposable elements in mammals and plants. While this epigenetic mark is extensively reprogrammed in the germline and early embryos of mammals, the extent to which DNA methylation is reset between generations in plants remains largely unknown. RESULTS:Using Arabidopsis as a model, we uncovered distinct DNA methylation dynamics over transposable element sequences during the early stages of plant development. Specifically, transposable elements and their relics show invariably high methylation at CG sites but increasing methylation at CHG and CHH sites. This non-CG methylation culminates in mature embryos, where it reaches saturation for a large fraction of methylated CHH sites, compared to the typical 10-20% methylation level observed in seedlings or adult plants. Moreover, the increase in CHH methylation during embryogenesis matches the hypomethylated state in the early endosperm. Finally, we show that interfering with the embryo-to-seedling transition results in the persistence of high CHH methylation levels after germination, specifically over sequences that are targeted by the RNA-directed DNA methylation (RdDM) machinery. CONCLUSION:Our findings indicate the absence of extensive resetting of DNA methylation patterns during early plant life and point instead to an important role of RdDM in reinforcing DNA methylation of transposable element sequences in every cell of the mature embryo. Furthermore, we provide evidence that this elevated RdDM activity is a specific property of embryogenesis. 10.1186/s13059-017-1313-0

Context-Dependent Developmental Effects of Parental Shade Versus Sun Are Mediated by DNA Methylation. Baker Brennan H,Berg Lars J,Sultan Sonia E Frontiers in plant science Parental environment influences progeny development in numerous plant and animal systems. Such inherited environmental effects may alter offspring phenotypes in a consistent way, for instance when resource-deprived parents produce low quality offspring due to reduced maternal provisioning. However, because development of individual organisms is guided by both inherited and immediate environmental cues, parental conditions may have different effects depending on progeny environment. Such context-dependent transgenerational plasticity suggests a mechanism of environmental inheritance that can precisely interact with immediate response pathways, such as epigenetic modification. We show that parental light environment (shade versus sun) resulted in context-dependent effects on seedling development in a common annual plant, and that these effects were mediated by DNA methylation. We grew replicate parents of five highly inbred genotypes in glasshouse shade versus sun and, in a fully factorial design, measured ecologically important traits of their isogenic seedling offspring in both environments. Compared to the offspring of sun-grown parents, the offspring of shade-grown parents produced leaves with greater mean and specific leaf area, and had higher total leaf area and biomass. These shade-adaptive effects of parental shade were pronounced and highly significant for seedlings growing in shade, but slight and generally non-significant for seedlings growing in sun. Based on both regression and covariate analysis, inherited effects of parental shade were not mediated by changes to seed provisioning. To test for a role of DNA methylation, we exposed replicate offspring of isogenic shaded and fully insolated parents to either the demethylating agent zebularine or to control conditions during germination, then raised them in simulated growth chamber shade. Partial demethylation of progeny DNA had no phenotypic effect on offspring of shaded parents, but caused offspring of sun-grown parents to develop as if their parents had been shaded, with larger leaves and greater total canopy area and biomass. These results contribute to the increasing body of evidence that DNA methylation can mediate transgenerational environmental effects, and show that such effects may contribute to nuanced developmental interactions between parental and immediate environments. 10.3389/fpls.2018.01251

Reversible DNA methylation regulates seasonal photoperiodic time measurement. Stevenson Tyler J,Prendergast Brian J Proceedings of the National Academy of Sciences of the United States of America In seasonally breeding vertebrates, changes in day length induce categorically distinct behavioral and reproductive phenotypes via thyroid hormone-dependent mechanisms. Winter photoperiods inhibit reproductive neuroendocrine function but cannot sustain this inhibition beyond 6 mo, ensuring vernal reproductive recrudescence. This genomic plasticity suggests a role for epigenetics in the establishment of seasonal reproductive phenotypes. Here, we report that DNA methylation of the proximal promoter for the type III deiodinase (dio3) gene in the hamster hypothalamus is reversible and critical for photoperiodic time measurement. Short photoperiods and winter-like melatonin inhibited hypothalamic DNA methyltransferase expression and reduced dio3 promoter DNA methylation, which up-regulated dio3 expression and induced gonadal regression. Hypermethylation attenuated reproductive responses to short photoperiods. Vernal refractoriness to short photoperiods reestablished summer-like methylation of the dio3 promoter, dio3 expression, and reproductive competence, revealing a dynamic and reversible mechanism of DNA methylation in the mammalian brain that plays a central role in physiological orientation in time. 10.1073/pnas.1310643110

Perceptions of epigenetics. Bird Adrian Nature Geneticists study the gene; however, for epigeneticists, there is no obvious 'epigene'. Nevertheless, during the past year, more than 2,500 articles, numerous scientific meetings and a new journal were devoted to the subject of epigenetics. It encompasses some of the most exciting contemporary biology and is portrayed by the popular press as a revolutionary new science--an antidote to the idea that we are hard-wired by our genes. So what is epigenetics? 10.1038/nature05913

Epigenetics and insect polyphenism: mechanisms and climate change impacts. Richard Gautier,Le Trionnaire Gaël,Danchin Etienne,Sentis Arnaud Current opinion in insect science Phenotypic plasticity is a ubiquitous process found in all living organisms. Polyphenism is an extreme case of phenotypic plasticity which shares a common scheme in insects such as honeybees, locusts or aphids: an initial perception of environmental stimuli, a neuroendocrine transmission of these signals to the target tissues, the activation of epigenetic mechanisms allowing the setup of alternative transcriptional programs responsible for the establishment of discrete phenotypes. Climate change can modulate the environmental stimuli triggering polyphenisms, and/or some epigenetics marks, thus modifying on the short and long terms the discrete phenotype proportions within populations. This might result in critical ecosystem changes. 10.1016/j.cois.2019.06.013

Can epigenetics translate environmental cues into phenotypes? Norouzitallab Parisa,Baruah Kartik,Vanrompay Daisy,Bossier Peter The Science of the total environment Living organisms are constantly exposed to wide ranges of environmental cues. They react to these cues by undergoing a battery of phenotypic responses, such as by altering their physiological and behavioral traits, in order to adapt and survive in the changed environments. The adaptive response of a species induced by environmental cues is typically thought to be associated with its genetic diversity such that higher genetic diversity provides increased adaptive potential. This originates from the general consensus that phenotypic traits have a genetic basis and are subject to Darwinian natural selection and Mendelian inheritance. There is no doubt about the validity of these principles, supported by the successful introgression of specific traits during (selective) breeding. However, a range of recent studies provided fascinating evidences suggesting that environmental effects experienced by an organism during its lifetime can have marked influences on its phenotype, and additionally the organism can pass on the acquired phenotypes to its subsequent generations through non-genetic mechanisms (also termed as epigenetic mechanism) - a notion that dates back to Lamarck and has been controversial ever since. In this review, we describe how the epigenetics has reshaped our long perception about the inheritance/development of phenotypes within organisms, contrasting with the classical gene-based view of inheritance. We particularly highlighted recent developments in our understanding of inheritance of parental environmental induced phenotypic traits in multicellular organisms under different environmental conditions, and discuss how modifications of the epigenome contribute to the determination of the adult phenotype of future generations. 10.1016/j.scitotenv.2018.08.063

The preconception environment and sperm epigenetics. Andrology BACKGROUND:Infertility is a common reproductive disorder, with male factor infertility accounting for approximately half of all cases. Taking a paternal perceptive, recent research has shown that sperm epigenetics, such as changes in DNA methylation, histone modification, chromatin structure, and noncoding RNA expression, can impact reproductive and offspring health. Importantly, environmental conditions during the preconception period has been demonstrated to shape sperm epigenetics. OBJECTIVES:To provide an overview on epigenetic modifications that regulate normal gene expression and epigenetic remodeling that occurs during spermatogenesis, and to discuss the epigenetic alterations that may occur to the paternal germline as a consequence of preconception environmental conditions and exposures. MATERIALS AND METHODS:We examined published literature available on databases (PubMed, Google Scholar, ScienceDirect) focusing on adult male preconception environmental exposures and sperm epigenetics in epidemiologic studies and animal models. RESULTS:The preconception period is a sensitive developmental window in which a variety of exposures such as toxicants, nutrition, drugs, stress, and exercise, affects sperm epigenetics. DISCUSSION AND CONCLUSION:Understanding the environmental legacy of the sperm epigenome during spermatogenesis will enhance our understanding of reproductive health and improve reproductive success and offspring well-being. 10.1111/andr.12753

Heat-induced release of epigenetic silencing reveals the concealed role of an imprinted plant gene. Sanchez Diego H,Paszkowski Jerzy PLoS genetics Epigenetic mechanisms suppress the transcription of transposons and DNA repeats; however, this suppression can be transiently released under prolonged heat stress. Here we show that the Arabidopsis thaliana imprinted gene SDC, which is silent during vegetative growth due to DNA methylation, is activated by heat and contributes to recovery from stress. SDC activation seems to involve epigenetic mechanisms but not canonical heat-shock perception and signaling. The heat-mediated transcriptional induction of SDC occurs particularly in young developing leaves and is proportional to the level of stress. However, this occurs only above a certain window of absolute temperatures and, thus, resembles a thermal-sensing mechanism. In addition, the re-silencing kinetics during recovery can be entrained by repeated heat stress cycles, suggesting that epigenetic regulation in plants may conserve memory of stress experience. We further demonstrate that SDC contributes to the recovery of plant biomass after stress. We propose that transcriptional gene silencing, known to be involved in gene imprinting, is also co-opted in the specific tuning of SDC expression upon heat stress and subsequent recovery. It is therefore possible that dynamic properties of the epigenetic landscape associated with silenced or imprinted genes may contribute to regulation of their expression in response to environmental challenges. 10.1371/journal.pgen.1004806

Pattern-Triggered Immunity and Effector-Triggered Immunity: crosstalk and cooperation of PRR and NLR-mediated plant defense pathways during host-pathogen interactions. Physiology and molecular biology of plants : an international journal of functional plant biology The elucidation of the molecular basis underlying plant-pathogen interactions is imperative for the development of sustainable resistance strategies against pathogens. Plants employ a dual-layered immunological detection and response system wherein cell surface-localized Pattern Recognition Receptors (PRRs) and intracellular Nucleotide-Binding Leucine-Rich Repeat Receptors (NLRs) play pivotal roles in initiating downstream signalling cascades in response to pathogen-derived chemicals. Pattern-Triggered Immunity (PTI) is associated with PRRs and is activated by the recognition of conserved molecular structures, known as Pathogen-Associated Molecular Patterns. When PTI proves ineffective due to pathogenic effectors, Effector-Triggered Immunity (ETI) frequently confers resistance. In ETI, host plants utilize NLRs to detect pathogen effectors directly or indirectly, prompting a rapid and more robust defense response. Additionally epigenetic mechanisms are participating in plant immune memory. Recently developed technologies like CRISPR/Cas9 helps in exposing novel prospects in plant pathogen interactions. In this review we explore the fascinating crosstalk and cooperation between PRRs and NLRs. We discuss epigenomic processes and CRISPR/Cas9 regulating immune response in plants and recent findings that shed light on the coordination of these defense layers. Furthermore, we also have discussed the intricate interactions between the salicylic acid and jasmonic acid signalling pathways in plants, offering insights into potential synergistic interactions that would be harnessed for the development of novel and sustainable resistance strategies against diverse group of pathogens. 10.1007/s12298-024-01452-7

A Polycomb-based switch underlying quantitative epigenetic memory. Angel Andrew,Song Jie,Dean Caroline,Howard Martin Nature The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with stable epigenetic silencing. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between them. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming. 10.1038/nature10241

Exposome and Immunity Training: How Pathogen Exposure Order Influences Innate Immune Cell Lineage Commitment and Function. Adams Kevin,Weber K Scott,Johnson Steven M International journal of molecular sciences Immune memory is a defining characteristic of adaptive immunity, but recent work has shown that the activation of innate immunity can also improve responsiveness in subsequent exposures. This has been coined "trained immunity" and diverges with the perception that the innate immune system is primitive, non-specific, and reacts to novel and recurrent antigen exposures similarly. The "exposome" is the cumulative exposures (diet, exercise, environmental exposure, vaccination, genetics, etc.) an individual has experienced and provides a mechanism for the establishment of immune training or immunotolerance. It is becoming increasingly clear that trained immunity constitutes a delicate balance between the dose, duration, and order of exposures. Upon innate stimuli, trained immunity or tolerance is shaped by epigenetic and metabolic changes that alter hematopoietic stem cell lineage commitment and responses to infection. Due to the immunomodulatory role of the exposome, understanding innate immune training is critical for understanding why some individuals exhibit protective phenotypes while closely related individuals may experience immunotolerant effects (e.g., the order of exposure can result in completely divergent immune responses). Research on the exposome and trained immunity may be leveraged to identify key factors for improving vaccination development, altering inflammatory disease development, and introducing potential new prophylactic treatments, especially for diseases such as COVID-19, which is currently a major health issue for the world. Furthermore, continued exposome research may prevent many deleterious effects caused by immunotolerance that frequently result in host morbidity or mortality. 10.3390/ijms21228462

Superovulation induces alterations in the epigenome of zygotes, and results in differences in gene expression at the blastocyst stage in mice. Huffman Sarah Rose,Pak Youngju,Rivera Rocío Melissa Molecular reproduction and development Gamete and embryo manipulations can result in alterations to the epigenome, and are associated with altered gene expression. The initial objective of this study was to determine the transcript level of several epigenetic modifiers in embryos that had been cultured from the 2-cell stage until the late-blastocyst stage in four culture conditions. Cultured embryos were compared to control, in vivo-produced late blastocysts to ascertain if differences in gene expression existed among the culture conditions; none were observed. As all of the embryos used were produced in females that had undergone superovulation, we next compared the transcript level of the same epigenetic modifiers between superovulated, in vivo-produced embryos and embryos produced from natural ovulation. Following in vitro culturing, expression of the genes analyzed was increased in all superovulation groups. We therefore hypothesized that the superovulation procedure-used to increase the number of embryos obtained for experimentation-may have caused an inappropriate acquisition of epigenetic modifications in the maternal genome prior to ovulation, which in turn caused misexpression of genes at the blastocyst stage. To test this hypothesis, we compared the level of global DNA methylation and histone 3 lysine-9 or -14 acetylation in zygotes obtained by natural- or superovulation. Indeed, superovulation decreased global DNA methylation on the maternal pronucleus of zygotes, which inversely correlated with H3K9/14 acetylation. In conclusion, superovulation alters the epigenome of the oocyte, resulting in the dysregulation of gene expression at the blastocyst stage. 10.1002/mrd.22463

Control of Mammalian Oocyte Development by Interactions with the Maternal Follicular Environment. Clarke Hugh Results and problems in cell differentiation Development of animal germ cells depends critically on continuous contact and communication with the somatic compartment of the gonad. In females, each oocyte is enclosed within a follicle, whose somatic cells supply nutrients that sustain basal metabolic activity of the oocyte and send signals that regulate its differentiation. This maternal microenvironment thus plays an indispensable role in ensuring the production of fully differentiated oocytes that can give rise to healthy embryos. The granulosa cells send signals, likely membrane-associated Kit ligand, which trigger oocytes within resting-stage primordial follicles to initiate growth. During growth, the granulosa cells feed amino acids, nucleotides, and glycolytic substrates to the oocyte. These factors are necessary for the oocyte to complete its growth and are delivered via gap junctions that couple the granulosa cells to the oocyte. In a complementary manner, growing oocytes also release growth factors, notably growth-differentiation factor 9 and bone morphogenetic protein 15, which are necessary for proper differentiation of the granulosa cells and for these cells to support oocyte growth. During the late stages of oocyte growth, cyclic GMP that is synthesized by the granulosa cells and diffuses into the oocyte is required to prevent its precocious entry into meiotic maturation. Finally, at the early stages of maturation, granulosa cell signals promote the synthesis of a subset of proteins within the oocyte that enhance their ability to develop as embryos. Thus, the maternal legacy of the follicular microenvironment is witnessed by the fertilization of the ovulated oocyte and subsequent birth of healthy offspring. 10.1007/978-3-319-60855-6_2

Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth. McPherson Nicole O,Bakos Hassan W,Owens Julie A,Setchell Brian P,Lane Michelle PloS one Paternal obesity is now clearly associated with or causal of impaired embryo and fetal development and reduced pregnancy rates in humans and rodents. This appears to be a result of reduced blastocyst potential. Whether these adverse embryo and fetal outcomes can be ameliorated by interventions to reduce paternal obesity has not been established. Here, male mice fed a high fat diet (HFD) to induce obesity were used, to determine if early embryo and fetal development is improved by interventions of diet (CD) and/or exercise to reduce adiposity and improve metabolism. Exercise and to a lesser extent CD in obese males improved embryo development rates, with increased cell to cell contacts in the compacting embryo measured by E-cadherin in exercise interventions and subsequently, increased blastocyst trophectoderm (TE), inner cell mass (ICM) and epiblast cell numbers. Implantation rates and fetal development from resulting blastocysts were also improved by exercise in obese males. Additionally, all interventions to obese males increased fetal weight, with CD alone and exercise alone, also increasing fetal crown-rump length. Measures of embryo and fetal development correlated with paternal measures of glycaemia, insulin action and serum lipids regardless of paternal adiposity or intervention, suggesting a link between paternal metabolic health and subsequent embryo and fetal development. This is the first study to show that improvements to metabolic health of obese males through diet and exercise can improve embryo and fetal development, suggesting such interventions are likely to improve offspring health. 10.1371/journal.pone.0071459

Impact of linoleic acid on bovine oocyte maturation and embryo development. Marei Waleed F,Wathes D Claire,Fouladi-Nashta Ali A Reproduction (Cambridge, England) Linoleic acid (LA; 18:2 n-6) is the most abundant fatty acid in bovine follicular fluid, and it was previously reported that LA concentration significantly decreases when follicle size increases. This suggests that LA may have a role in the regulation of oocyte maturation. The present study investigated the effect of LA supplementation on bovine oocyte maturation and early embryo development in vitro. Treatment of cumulus-oocyte complexes (COCs) with LA significantly inhibited cumulus cell expansion and retarded development of the oocytes to the metaphase II (MII) stage in a dose-dependent manner. This effect was reversible, and the oocytes developed to the MII stage after extended culture in the absence of LA. Treatment of COCs with LA also resulted in a significantly lower percentage of cleaved embryos and blastocyst yield. Furthermore, COCs treated with LA had significant effects compared with controls in i) increasing prostaglandin E(2) concentration in the medium, ii) decreasing intracellular cAMP at 6 and 24 h of maturation and iii) decreasing phosphorylation of the MAPK1 and 3 at 24 h, and AKT at 6 h of maturation. In conclusion, LA supplementation to bovine oocytes during maturation altered the molecular mechanisms regulating oocyte maturation and resulted in decreased percentage of oocytes at MII stage and inhibition of the subsequent early embryo development. These data provide evidence for adverse effects of LA on oocyte development, which can be associated with dietary increased level of LA in the follicular fluid and the decline in fertility in farm animals and human. 10.1530/REP-09-0503

Adaptive responses of the embryo to maternal diet and consequences for post-implantation development. Fleming Tom P,Lucas Emma S,Watkins Adam J,Eckert Judith J Reproduction, fertility, and development Maternal periconceptional (PC) nutrition, coupled with maternal physiological condition, can impact on reproductive performance and potential across mammalian species. Oocyte quality and embryo development are affected adversely by either nutrient restriction or excess. Moreover, the quality of maternal PC nutrition can have lasting effects through fetal development and postnatally into adulthood. Chronic disease, notably cardiovascular and metabolic disease, and abnormal behaviour have been identified in adult offspring in small and large animal models of PC nutrient restriction. These long-term effects associate with compensatory responses that begin from the time of early embryo development. This review assesses the field of PC nutrition in vivo on short- and long-term developmental consequences in rodent and ruminant models and considers the implications for human health. 10.1071/RD11905

Starvation during pregnancy impairs fetal oogenesis and folliculogenesis in offspring in the mouse. Wang Jun-Jie,Yu Xiao-Wei,Wu Rui-Ying,Sun Xiao-Feng,Cheng Shun-Feng,Ge Wei,Liu Jing-Cai,Li Ya-Peng,Liu Jing,Zou Shu-Hua,De Felici Massimo,Shen Wei Cell death & disease Although it is becoming increasingly evident that maternal starvation during pregnancy can have permanent effects on a range of physiological processes in the offspring, scant information is available about the consequence of such condition for oogenesis and hence for lifetime reproductive success of progeny in mammals. In the present study, we address this topic by starving pregnant mice at the time of ovarian differentiation (12.5 days post coitum (dpc)) for three consecutive days and analyzed the consequence first on the survival of the fetal oocytes and their capability to progress throughout the stages of meiotic prophase I (MPI) and then on the postnatal folliculogenesis of the offspring. The results showed that maternal starvation increased apoptosis in the fetal ovaries, resulting in reduction of the oocyte number. Moreover, MPI progression was slowed down in the surviving oocytes and the expression of DNA repair players in the starved ovaries increased. Transcriptome analysis identified 61 differentially expressed genes between control and starved ovaries, the most part of these being involved in metabolic processes. A significant decrease in the percentage of oocytes enclosed in primordial follicles and the expression of oocyte genes critically involved in folliculogenesis such as Nobox, Lhx8 and Sohlh2 in the 3 days post partum (dpp) starved ovaries were found. Finally, at the time of juvenile period (21 dpp), the number of oocytes and antral follicles resulted significantly lower in the ovaries of the offspring from starved mothers in comparison to controls. Our findings support the notion that maternal starvation can affect ovary development in the offspring that could adversely affect their reproductive success in the adult life. 10.1038/s41419-018-0492-2

Effects of differing oocyte-secreted factors during mouse in vitro maturation on subsequent embryo and fetal development. Sudiman J,Ritter L J,Feil D K,Wang X,Chan K,Mottershead D G,Robertson D M,Thompson J G,Gilchrist R B Journal of assisted reproduction and genetics PURPOSE:We hypothesised that varying native oocyte-secreted factor (OSF) exposure or using different recombinant OSF peptides would have differential effects on post-in vitro maturation (IVM) embryo and fetal development. METHODS:Mouse cumulus oocyte complexes (COCs) were treated with the purified mature domain of GDF9 and/or BMP15 or were co-cultured with denuded oocytes (DOs) from 0 h or 3 h of IVM. DOs were matured for 3 h as either intact COCs+/-FSH before denuding, or as DOs + FSH. COCs were fertilised and blastocyst development was assessed on days 5 and 6, and either differentially stained for ICM numbers or vitrified/warmed embryos were transferred to recipients to assess implantation and fetal rates. RESULTS:No improvement in embryo development was observed with the addition of GDF9 and/or BMP15 to IVM. In contrast, embryos derived from COCs co-cultured with DOs had significantly improved blastocyst rates and ICM numbers compared to controls (P < 0.05). The highest response was obtained when DOs were first added to COCs at 3 h of IVM, after being pre-treated (0-3 h) as COCs + FSH. Compared to control, co-culture with DOs from 3 h did not affect implantation rates but more than doubled fetal yield (21% vs 48%; P < 0.05). GDF9 Western blot analysis was unable to detect any differences in quantity or form of GDF9 (17 and 65 kDa) in extracts of DO at 0 h or 3 h. CONCLUSIONS:This study provides new knowledge on means to improve oocyte quality in vitro which has the potential to significantly aid human infertility treatment and animal embryo production technologies. 10.1007/s10815-013-0152-5

Environmental perception and epigenetic memory: mechanistic insight through FLC. Berry Scott,Dean Caroline The Plant journal : for cell and molecular biology Chromatin plays a central role in orchestrating gene regulation at the transcriptional level. However, our understanding of how chromatin states are altered in response to environmental and developmental cues, and then maintained epigenetically over many cell divisions, remains poor. The floral repressor gene FLOWERING LOCUS C (FLC) in Arabidopsis thaliana is a useful system to address these questions. FLC is transcriptionally repressed during exposure to cold temperatures, allowing studies of how environmental conditions alter expression states at the chromatin level. FLC repression is also epigenetically maintained during subsequent development in warm conditions, so that exposure to cold may be remembered. This memory depends on molecular complexes that are highly conserved among eukaryotes, making FLC not only interesting as a paradigm for understanding biological decision-making in plants, but also an important system for elucidating chromatin-based gene regulation more generally. In this review, we summarize our understanding of how cold temperature induces a switch in the FLC chromatin state, and how this state is epigenetically remembered. We also discuss how the epigenetic state of FLC is reprogrammed in the seed to ensure a requirement for cold exposure in the next generation. 10.1111/tpj.12869

Oocyte and Embryo Manipulation and Epigenetics. Osman Emily,Franasiak Jason,Scott Richard Seminars in reproductive medicine Regulation of the epigenome is a mechanism by which the environment influences gene expression and consequently the health of the individual. The advent and refinement of novel assisted reproductive technology (ART) laboratory techniques, including vitrification, dynamic culture systems, oocyte in vitro maturation, laser-assisted hatching, intracytoplasmic sperm injection, and preimplantation genetic testing for aneuploidy have contributed to the success of ART. From fertilization through implantation, the epigenetic profile of the embryo changes dynamically. Concurrently with these changes, embryo development in vitro is dependent on laboratory intervention and manipulation to optimize outcomes. The impact of ART techniques on imprinting errors remains unclear, as the infertile population likely confers an independent risk factor for defects in expected epigenetic patterns. Alternations in epigenetic mechanisms may contribute to the incidence of aneuploidy as well as recurrent implantation failure of euploid embryos. Additional investigative efforts are needed to assess the contribution of oocyte and embryo manipulation on imprinting modifications in this vulnerable population. The development of diagnostic modalities involving the discovery of epigenetic alterations to improve in vitro fertilization outcomes is an exciting and promising area of future study. 10.1055/s-0039-1688801

[DOHaD and pre- or peri-conceptional programming]. Chavatte-Palmer Pascale,Vialard François,Tarrade Anne,Dupont Charlotte,Duranthon Véronique,Lévy Rachel Medecine sciences : M/S The pre- and peri-conceptional periods (before and just after fertilization, until the blastocyst stage) are critical in the context of the Developmental Origins of Health and Disease (DOHaD). Maternal in vivo environment, in particular nutrition, can disturb the apposition of epigenetic marks throughout gametogenesis, fertilization and the first steps of embryonic development, which are times during which major epigenetic changes take place. The in vitro environment, in the case of assisted reproduction techniques, also affects epigenetic marks. Whilst the embryo is a target of these changes, female and male gametes are both target and vector of these epigenetic changes, thus leading to multigenerational effects. Long term consequences on the phenotype of offspring vary according to the sex of the vector parent, the sex of the individual and the generation. 10.1051/medsci/20163201010