Epigenetic Inheritance Research Articles

GPX3 expression was down-regulated but positively correlated with poor outcome in human cancers.

Cancer is a crucial public health problem and one of the leading causes of death worldwide. Previous studies have suggested that GPX3 may be involved in cancer metastasis and chemotherapy resistance. However, how GPX3 affects cancer patients' outcomes and the underlying mechanism remains unclear. Sequencing data and clinical data from TCGA, GTEx, HPA, and CPTAC were used to explore the relationship between GPX3 expression and clinical features. Immunoinfiltration scores were used to assess the relationship between GPX3 and the tumor immune microenvironment. Functional enrichment analysis was used to predict the role of GPX3 in tumors. Gene mutation frequency, methylation level, and histone modification were used to predict the GPX3 expression regulation method. Breast, ovarian, colon, and gastric cancer cells were used to investigate the relationship between GPX3 expression and cancer cell metastasis, proliferation, and chemotherapy sensitivity. GPX3 is down-regulated in various tumor tissues, and GPX3 expression level can be used as a marker for cancer diagnosis. However, GPX3 expression is associated with higher stage and lymph node metastasis, as well as poorer prognosis. GPX3 is closely related to thyroid function and antioxidant function, and its expression may be regulated by epigenetic inheritance such as methylation modification or histone modification. In vitro experiments, GPX3 expression is associated with cancer cell sensitivity to oxidant and platinum-based chemotherapy and is involved in tumor metastasis in oxidative environments. We explored the relationship between GPX3 and clinical features, immune infiltration characteristics, migration and metastasis, and chemotherapy sensitivities of human cancers. We further investigated the potential genetic and epigenetic regulation of GPX3 in cancer. Our results suggested that GPX3 plays a complicated role in the tumor microenvironment, simultaneously promoting metastasis and chemotherapy resistance in human cancers.

Significance of preventing developmental origins of diseases in improving population quality

More studies show that various diseases, especially chronic non-infectious diseases, have developmental origin. Developmental origins of diseases are mainly due to gametes and early life development stage being exposed to adverse environment, resulting in abnormal modification of epigenetic and stable inheritance to the adult stage, which could make the risk of various long-term diseases of individuals high. The theory of developmental origin provides a new perspective for the occurrence and development of diseases, and also provides a theoretical basis for disease prevention. Attaching importance to maternal and child health care and life-cycle management is conducive to the prevention of developmental diseases and is of great significance to the improvement of population quality.

Recycling of parental histones preserves the epigenetic landscape during embryonic development.

Epigenetic inheritance during DNA replication requires an orchestrated assembly of nucleosomes from parental and newly synthesized histones. We analyzed Drosophila HisC mutant embryos harboring a deletion of all canonical histone genes, in which nucleosome assembly relies on parental histones from cell cycle 14 onward. Lack of new histone synthesis leads to more accessible chromatin and reduced nucleosome occupancy, since only parental histones are available. This leads to up-regulated and spurious transcription, whereas the control of the developmental transcriptional program is partially maintained. The genomic positions of modified parental histone H2A, H2B, and H3 are largely restored during DNA replication. However, parental histones with active marks become more dispersed within gene bodies, which is linked to transcription. Together, the results suggest that parental histones are recycled to preserve the epigenetic landscape during DNA replication in vivo.

Dietary trends and the decline in male reproductive health.

Over the twentieth century, male reproductive health has suffered a substantial decline, as evidenced by decreases in sperm counts and testosterone levels and increases in reproductive pathologies. At the same time, the prevalence of chronic diseases such as obesity, diabetes, and metabolic syndrome has risen dramatically. Metabolic and reproductive health are highly interconnected, suggesting that their respective trends are intertwined and, given the timeframe of such trends, environmental and not genetic factors are most likely to be the primary causes. Industrialization, which began in Europe in the mid-eighteenth century, has resulted in profound changes to our diet, lifestyle, and environment, many of which are causal factors in the rise in chronic diseases. Industrialization results in a nutrition transition from an agricultural unprocessed to a modern processed diet, incorporating increases in sugar, vegetable oils, ultra-processed foods, linoleic acid, trans-fats, and total energy. This dietary shift has incurred numerous adverse effects on metabolic and reproductive health, characterized by chronic inflammation, oxidative stress, and insulin resistance. Moreover, these effects appear to multiply across subsequent generations via epigenetic inheritance. Men's fertility is markedly affected by obesity and diabetes, with an increase in total energy via processed food intake arguably being the key factor driving the diabesity pandemic. In contrast, wholefoods rich in micronutrients and phytonutrients support male fertility and a healthy body weight. Therefore, men wanting to maximize their fertility should consider making positive dietary changes, such as replacing processed foods with unprocessed foods that support metabolic and reproductive health.

Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice

Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.

Induced epigenetic changes memorized across generations in mice.

Transgenerational epigenetic inheritance in mammals has long been debatable. In this issue of Cell, Takahashi etal. induce DNA methylation at promoter-associated CpG islands (CGIs) of two metabolism-related genes and show that the acquired epigenetic changes and associated metabolic phenotypes are stably propagated across several generations in transgenic mice.

Identifying the role of the FACT histone chaperone in epigenetics through single-molecule fluorescence imaging.

Modifications of histones in eukaryotic cells lead to reversible changes in gene expression without altering the genetic code itself. Such epigenetic modifications are necessary for the proper functioning of cellular processes like gene expression, DNA repair, and cell division. Modified histones directly affect chromatin dynamics and promote other regulation factors such as chromatin remodelers, including histone chaperones. Histone chaperones make functional DNA templates that maintain epigenetic information by remodeling the nucleosome during essential life processes, such as transcription and replication, and by avoiding histone aggregation. The facilitates chromatin transcription (FACT) histone chaperone includes two essential proteins, Pob3 and Spt16. Previously, we found that deleting Pob3 suppresses epigenetic inheritance, indicating that FACT plays an important role in epigenetic maintenance. Therefore, we engineered Schizosaccharomyces pombe (fission yeast) cell strains that express fusions of Spt16 or Pob3 to the fluorescent protein PAmCherry and investigated the dynamics of single proteins in the FACT complex in living S. pombe cells to identify the mechanism for this epigenetic inheritance suppression, including measuring changes in interactions during transcription and replication. By analyzing the motion of Spt16-PAmCherry single-molecule trajectories with nonparametric Bayesian statistics, we were able to distinguish three types of single-molecule motion: a fast (free) mobility state, an intermediate (transiently bound) mobility state, and a slow (bound) mobility state. We are assigning these biophysical states to specific biochemical processes by constructing Spt16 and Pob3 mutants with impaired histone protein binding properties, as well as drug-susceptible strains in which we can inhibit transcription and replication to identify changes in the FACT protein mobility. Overall, our live-cell single-molecule experiments reveal how the FACT complex interacts with histones and other chaperones and indicate a mechanism for epigenetic maintenance.

Transcriptome profiling of histone writers/erasers enzymes across spermatogenesis, mature sperm and pre-cleavage embryo: Implications in paternal epigenome transitions and inheritance mechanisms.

Accumulating evidence points out that sperm carry epigenetic instructions to embryo in the form of retained histones marks and RNA cargo that can transmit metabolic and behavioral traits to offspring. However, the mechanisms behind epigenetic inheritance of paternal environment are still poorly understood. Here, we curated male germ cells RNA-seq data and analyzed the expression profile of all known histone lysine writers and erasers enzymes across spermatogenesis, unraveling the developmental windows at which they are upregulated, and the specific activity related to canonical and non-canonical histone marks deposition and removal. We also characterized the epigenetic enzymes signature in the mature sperm RNA cargo, showing most of them positive translation at pre-cleavage zygote, suggesting that paternally-derived enzymes mRNA cooperate with maternal factors to embryo chromatin assembly. Our study shows several histone modifying enzymes not described yet in spermatogenesis and even more, important mechanistic aspects behind transgenerational epigenetics. Epigenetic enzymes not only can respond to environmental stressors, but could function as vectors of epigenetic information and participate in chromatin organization during maternal-to-zygote transition.

Men who inject opioids exhibit altered tRNA-Gly-GCC isoforms in semen.

In addition to their role in protein translation, tRNAs can be cleaved into shorter, biologically active fragments called tRNA fragments (tRFs). Specific tRFs from spermatocytes can propagate metabolic disorders in second generations of mice. Thus, tRFs in germline cells are a mechanism of epigenetic inheritance. It has also been shown that stress and toxins can cause alterations in tRF patterns. We were therefore interested in whether injecting illicit drugs, a major stressor, impacts tRFs in germline cells. We sequenced RNA from spermatocytes and from semen-derived exosomes from people who inject illicit drugs (PWID) and from non-drug using controls, both groups of unknown fertility status. All PWID injected opioids daily, but most also used other illicit drugs. The tRF cleavage products from Gly-GCC tRNA were markedly different between spermatocytes from PWID compared to controls. Over 90% of reads in controls mapped to shorter Gly-GCC tRFs, while in PWID only 45% did. In contrast, only 4.1% of reads in controls mapped to a longer tRFs versus 45.6% in PWID. The long/short tRF ratio was significantly higher in PWID than controls (0.23 versus 0.16, P = 0.0128). We also report differential expression of a group of small nucleolar RNAs (snoRNAs) in semen-derived exosomes, including, among others, ACA14a, U19, and U3-3. Thus, PWID exhibited an altered cleavage pattern of tRNA-Gly-GCC in spermatocytes and an altered cargo of snoRNAs in semen-derived exosomes. Participants were not exclusively using opioids and were not matched with controls in terms of diet, chronic disease, or other stressors, so our finding are not conclusively linked to opioid use. However, all individuals in the PWID group did inject heroin daily. Our study indicates a potential for opioid injection and/or its associated multi-drug use habits and lifestyle changes to influence epigenetic inheritance.

Transgenerational epigenetic inheritance of axonal regeneration after spinal cord injury.

Human epidemiological studies reveal that dietary and environmental alterations influence the health of the offspring and that the effect is not limited to the F1 or F2 generations. Non-Mendelian transgenerational inheritance of traits in response to environmental stimuli has been confirmed in non-mammalian organisms including plants and worms and are shown to be epigenetically mediated. However, transgenerational inheritance beyond the F2 generation remains controversial in mammals. Our lab previously discovered that the treatment of rodents (rats and mice) with folic acid significantly enhances the regeneration of injured axons following spinal cord injury in vivo and in vitro, and the effect is mediated by DNA methylation. The potential heritability of DNA methylation prompted us to investigate the following question: Is the enhanced axonal regeneration phenotype inherited transgenerationally without exposure to folic acid supplementation in the intervening generations? In the present review, we condense our findings showing that a beneficial trait (i.e., enhanced axonal regeneration after spinal cord injury) and accompanying molecular alterations (i.e., DNA methylation), triggered by an environmental exposure (i.e., folic acid supplementation) to F0 animals only, are inherited transgenerationally and beyond the F3 generation.

Role of epigenetics in the etiology of hypospadias through penile foreskin DNA methylation alterations

Abnormal penile foreskin development in hypospadias is the most frequent genital malformation in male children, which has increased dramatically in recent decades. A number of environmental factors have been shown to be associated with hypospadias development. The current study investigated the role of epigenetics in the etiology of hypospadias and compared mild (distal), moderate (mid shaft), and severe (proximal) hypospadias. Penile foreskin samples were collected from hypospadias and non-hypospadias individuals to identify alterations in DNA methylation associated with hypospadias. Dramatic numbers of differential DNA methylation regions (DMRs) were observed in the mild hypospadias, with reduced numbers in moderate and low numbers in severe hypospadias. Atresia (cell loss) of the principal foreskin fibroblast is suspected to be a component of the disease etiology. A genome-wide (> 95%) epigenetic analysis was used and the genomic features of the DMRs identified. The DMR associated genes identified a number of novel hypospadias associated genes and pathways, as well as genes and networks known to be involved in hypospadias etiology. Observations demonstrate altered DNA methylation sites in penile foreskin is a component of hypospadias etiology. In addition, a potential role of environmental epigenetics and epigenetic inheritance in hypospadias disease etiology is suggested.

Paternal Inheritance Is an Important, but Overlooked, Factor Affecting the Adverse Effects of Microplastics and Nanoplastics on Subsequent Generations.

Microplastics (MPs) and nanoplastics (NPs) are widely detected in food and the human environment. More studies have begun to pay attention to the influence of MPs and NPs on genetics; in particular, exposure of paternal generation to MPs and NPs on epigenetic inheritance and the offspring of animal models have attracted considerable interest. In this Viewpoint, we mainly discuss the suggestion that reproductive genetic changes in the male parent have the potential to be transferred to the offspring and illustrate how MPs and NPs in the father tissues are distributed in later generations. We provide a systematic understanding of the potential health hazards of paternal exposure to MPs and NPs to subsequent generations and put forth recommendations about the epigenetic effects for future research on public health and food safety.

Aging affects gene expression in spermatids of Brown Norway rats

The effects of aging on the reproductive health of men and the consequences for their offspring are becoming more widely recognized. Correlative epidemiological studies examining paternal age and offspring health suggest there are more frequent occurrences of genetic disorders in the children of older fathers. Given the genetic basis for paternal age-related disorders, we aim to characterize gene expression in developing germ cells. Round spermatids (RS) were collected from young (mean = 5.3 months) and aged (mean = 19.5 months) Brown Norway rats, representative of humans aged 20–30 years and 55+ years, respectively. Gene expression data were obtained by mRNA sequencing (n = 5), and were analysed for differential expression. Sequencing data display 211 upregulated and 9 downregulated transcripts in RS of aged rats, compared to young (log2FC >1, p < 0.05). Transcripts with increased expression are involved in several processes including sperm motility/morphology, sperm-egg binding, capacitation, and epigenetic inheritance. In addition, there are numerous dysregulated transcripts that regulate germ cell epigenetic marks and Sertoli-germ cell binding and communication. These results show an overall increase in RS gene expression with age, with spermatogenic functions being perturbed. Taken together, these findings help identify the genetic origin of the fertility, germ cell niche, and epigenetic effects observed with advanced paternal aging.

I4mC-CPXG: A Computational Model for Identifying DNA N4- methylcytosine Sites in Rosaceae Genome Using Novel Encoding Strategy

Background: N4-methylcytosine (4mC) is one of the most widespread DNA methylation modifications, which plays an important role in DNA replication and repair, epigenetic inheritance, gene expression levels and regulation of transcription. Although biological experiments can identify potential 4mC modification sites, they are limited due to the experimental environment and labor intensive. Therefore, it is crucial to construct a computational model to identify the 4mC sites. background: N4-methylcytosine (4mC) is one of the most widespread DNA methylation modifications, which plays an important role in DNA replication and repair, epigenetic inheritance, gene expression levels and regulation of transcription. Although biological experiment can identify potential 4mC modification sites, it’s limited due to the experimental environment and labor intensive. Therefore, it is crucial to construct a computational model to identify the 4mC sites. Objective: Although some computational methods have been proposed to identify the 4mC sites, some problems should not be ignored, such as: (1) a large number of unknown nucleotides exist in the biological sequence; (2) a large number of zeros exist in the previous encoding technologies; (3) sequence distribution information is important to identify 4mC sites. Considering these aspects, we propose a computational model based on a novel encoding strategy with position specific information to identify 4mC sites. Methods: We constructed an accurate computational model i4mC-CPXG based on extreme gradient boosting. Two aspects of feature vectors are extracted according to nucleotide information and position specific information. From the aspect of nucleotide information, we used prior information to identify the base type of unknown nucleotide and decrease the influence of invalid information caused by lots of zeros. From the aspect of position specific information, the vector was designed carefully to express the base distribution and arrangement. Then the feature vector fused by nucleotide information and position specific information was input into extreme gradient boosting to construct the model. method: We constructed an accurate computational model i4mC-CPXG based on extreme gradient boosting. Two aspects feature vectors are extracted according to nucleotide information and position specific information. From the aspect of nucleotide information, we used prior information to identify the base type of unknown nucleotide and decrease the influence of invalid information caused by lots of zeros. From the aspect of position specific information, the vector was designed carefully to express the base distribution and arrangement. Then the feature vector fused by nucleotide information and position specific information was input into extreme gradient boosting to construct model. Results: The accuracy of i4mC-CPXG is 82.49% on independent dataset. The result was better than model i4mC-w2vec which was the best model in the imbalanced dataset with the ratio of 1:15. Meanwhile, our model achieved good performance on other species. These results validated the effectiveness of i4mC-CPXG. Conclusion: Our method is effective to identify potential 4mC modification sites due to the proposed new encoding strategy fused position specific information. The satisfactory prediction results of balanced datasets, imbalanced datasets and other species datasets indicate that i4mC-CPXG is valuable to provide a reasonable supplement for biology research. other: The satisfactory prediction results of balanced datasets, imbalanced datasets and other species datasets indicate that i4mC-CPXG is valuable to provide a reasonable supplement for biology research.

Epigenetic control of heredity.

Epigenetics is the field of science that deals with the study of changes in gene function that do not involve changes in DNA sequence and are heritable while epigenetics inheritance is the process of transmission of epigenetic modifications to the next generation. It can be transient, intergenerational, or transgenerational. There are various epigenetic modifications involving mechanisms such as DNA methylation, histone modification, and noncoding RNA expression, all of which are inheritable. In this chapter, we summarize the information on epigenetic inheritance, its mechanism, inheritance studies on various organisms, factors affecting epigenetic modifications and their inheritance, and the role of epigenetic inheritance in the heritability of diseases.

Epigenetic inheritance of gene silencing is maintained by a self-tuning mechanism based on resource competition

Biological systems can maintain memories over long timescales, with examples including memories in the brain and immune system. It is unknown how functional properties of memory systems, such as memory persistence, can be established by biological circuits. To address this question, we focus on transgenerational epigenetic inheritance in Caenorhabditis elegans. In response to a trigger, worms silence a target gene for multiple generations, resisting strong dilution due to growth and reproduction. Silencing may also be maintained indefinitely upon selection according to silencing levels. We show that these properties imply the fine-tuning of biochemical rates in which the silencing system is positioned near the transition to bistability. We demonstrate that this behavior is consistent with a generic mechanism based on competition for synthesis resources, which leads to self-organization around a critical state with broad silencing timescales. The theory makes distinct predictions and offers insights into the design principles of long-term memory systems.

Transgenerational Epigenetic Inheritance of Traumatic Experience in Mammals.

In recent years, we have seen an increasing amount of evidence pointing to the existence of a non-genetic heredity of the effects of events such as separation from parents, threat to life, or other traumatising experiences such as famine. This heredity is often mediated by epigenetic regulations of gene expression and may be transferred even across several generations. In this review, we focus on studies which involve transgenerational epigenetic inheritance (TEI), with a short detour to intergenerational studies focused on the inheritance of trauma or stressful experiences. The reviewed studies show a plethora of universal changes which stress exposure initiates on multiple levels of organisation ranging from hormonal production and the hypothalamic-pituitary-adrenal (HPA) axis modulation all the way to cognition, behaviour, or propensity to certain psychiatric or metabolic disorders. This review will also provide an overview of relevant methodology and difficulties linked to implementation of epigenetic studies. A better understanding of these processes may help us elucidate the evolutionary pathways which are at work in the course of emergence of the diseases and disorders associated with exposure to trauma, either direct or in a previous generation.

Epigenetic Inheritance and the Modern Evolutionary Synthesis

Epigenetic Inheritance and the Modern Evolutionary Synthesis

Abstract 1189: Transgenerational epigenetic inheritance of obesogenic traits in a C. elegans model

Abstract 1189: Transgenerational epigenetic inheritance of obesogenic traits in a C. elegans model

Applications of bioinformatics in epigenetics.

Epigenetic modifications such as DNA methylation, post-translational chromatin modifications and non-coding RNA-mediated mechanisms are responsible for epigenetic inheritance. Change in gene expression due to these epigenetic modifications are responsible for new traits in different organisms leading to various diseases including cancer, diabetic kidney disease (DKD), diabetic nephropathy (DN) and renal fibrosis. Bioinformatics is an effective approach for epigenomic profiling. These epigenomic data can be analyzed by a large number of bioinformatics tools and software. Many databases are available online, which comprises huge amount of information regarding these modifications. Recent methodologies include many sequencing and analytical techniques to extrapolate different types of epigenetic data. This data can be used to design drugs against diseases linked to epigenetic modifications. This chapter briefly highlights different epigenetics databases (MethDB, REBASE, Pubmeth, MethPrimerDB, Histone Database, ChromDB, MeInfoText database, EpimiR, Methylome DB, and dbHiMo), and tools (compEpiTools, CpGProD, MethBlAST, EpiExplorer, and BiQ analyzer), which are being utilized to retrieve the data and mechanistically analysis of epigenetics modifications.