Epigenetic Inheritance Research Articles

Exogenous Coronavirus Interacts With Endogenous Retrotransposon in Human Cells.

There is an increased global outbreak of diseases caused by coronaviruses affecting respiratory tracts of birds and mammals. Recent dangerous coronaviruses are MERS-CoV, SARS-CoV, and SARS-CoV-2, causing respiratory illness and even failure of several organs. However, profound impact of coronavirus on host cells remains elusive. In this study, we analyzed transcriptome of MERS-CoV, SARS-CoV, and SARS-CoV-2 infected human lung-derived cells, and observed that infection of these coronaviruses all induced increase of retrotransposon expression with upregulation of TET genes. Upregulation of retrotransposon was also observed in SARS-CoV-2 infected human intestinal organoids. Retrotransposon upregulation may lead to increased genome instability and enhanced expression of genes with readthrough from retrotransposons. Therefore, people with higher basal level of retrotransposon such as cancer patients and aged people may have increased risk of symptomatic infection. Additionally, we show evidence supporting long-term epigenetic inheritance of retrotransposon upregulation. We also observed chimeric transcripts of retrotransposon and SARS-CoV-2 RNA for potential human genome invasion of viral fragments, with the front and the rear part of SARS-CoV-2 genome being easier to form chimeric RNA. Thus, we suggest that primers and probes for nucleic acid detection should be designed in the middle of virus genome to identify live virus with higher probability. In summary, we propose our hypothesis that coronavirus invades human cells and interacts with retrotransposon, eliciting more severe symptoms in patients with underlying diseases. In the treatment of patients with coronavirus infection, it may be necessary to pay more attention to the potential harm contributed by retrotransposon dysregulation.

Exploring the Stress Impact in the Paternal Germ Cells Epigenome: Can Catecholamines Induce Epigenetic Reprogramming?

Spermatogenesis is characterized by unique epigenetic programs that enable chromatin remodeling and transcriptional regulation for proper meiotic divisions and germ cells maturation. Paternal lifestyle stressors such as diet, drug abuse, or psychological trauma can directly impact the germ cell epigenome and transmit phenotypes to the next generation, pointing to the importance of epigenetic regulation during spermatogenesis. It is established that environmental perturbations can affect the development and behavior of the offspring through epigenetic inheritance, including changes in small non-coding RNAs, DNA methylation, and histones post-translational modifications. But how male germ cells react to lifestyle stressors and encode them in the paternal epigenome is still a research gap. Most lifestyle stressors activate catecholamine circuits leading to both acute and long-term changes in neural functions, and epigenetic mechanisms show strong links to both long-term and rapid, dynamic gene expression regulation during stress. Importantly, the testis shares a molecular and transcriptional signature with the brain tissue, including a rich expression of catecholaminergic elements in germ cells that seem to respond to stressors with similar epigenetic and transcriptional profiles. In this minireview, we put on stage the action of catecholamines as possible mediators between paternal stress responses and epigenetic marks alterations during spermatogenesis. Understanding the epigenetic regulation in spermatogenesis will contribute to unravel the coding mechanisms in the transmission of the biological impacts of stress between generations.

Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring.

A father's lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes to impact embryonic gene expression and development. Here, we demonstrate that a folate-deficient (FD) dietalters histone H3 lysine 4 trimethylation (H3K4me3) in sperm at developmental genes and putative enhancers. A subset of H3K4me3 alterations in sperm are retained in the pre-implantation embryo and associated with deregulated embryonic gene expression. Using a genetic mouse model in which sires have pre-existing altered H3K4me2/3 in sperm, we show that a FD diet exacerbates alterations in sperm H3K4me3 and embryonic gene expression, leading to an increase in developmental defect severity. These findings imply that paternal H3K4me3 is transmitted to the embryo and influences gene expression and development. It further suggests that epigenetic errors can accumulate in sperm to worsen offspring developmental outcomes.

Avenues of reef-building coral acclimatization in response to rapid environmental change.

The swiftly changing climate presents a challenge to organismal fitness by creating a mismatch between the current environment and phenotypes adapted to historic conditions. Acclimatory mechanisms may be especially crucial for sessile benthic marine taxa, such as reef-building corals, where climate change factors including ocean acidification and increasing temperature elicit strong negative physiological responses such as bleaching, disease and mortality. Here, within the context of multiple stressors threatening marine organisms, I describe the wealth of metaorganism response mechanisms to rapid ocean change and the ontogenetic shifts in organism interactions with the environment that can generate plasticity. I then highlight the need to consider the interactions of rapid and evolutionary responses in an adaptive (epi)genetic continuum. Building on the definitions of these mechanisms and continuum, I also present how the interplay of the microbiome, epigenetics and parental effects creates additional avenues for rapid acclimatization. To consider under what conditions epigenetic inheritance has a more substantial role, I propose investigation into the offset of timing of gametogenesis leading to different environmental integration times between eggs and sperm and the consequences of this for gamete epigenetic compatibility. Collectively, non-genetic, yet heritable phenotypic plasticity will have significant ecological and evolutionary implications for sessile marine organism persistence under rapid climate change. As such, reef-building corals present ideal and time-sensitive models for further development of our understanding of adaptive feedback loops in a multi-player (epi)genetic continuum.

Pesticide-induced multigenerational effects on amphibian reproduction and metabolism

Underlying drivers of species extinctions need to be better understood for effective conservation of biodiversity. Nearly half of all amphibian species are at risk of extinction, and pollution may be a significant threat as seasonal high-level agrochemical use overlaps with critical windows of larval development. The potential of environmental chemicals to reduce the fitness of future generations may have profound ecological and evolutionary implications. This study characterized effects of male developmental exposure to environmentally relevant concentrations of the anti-androgenic pesticide linuron over two generations of offspring in Xenopus tropicalis frogs. The adult male offspring of pesticide-exposed fathers (F1) showed reduced body size, decreased fertility, and signs of endocrine system disruption. Impacts were further propagated to the grand-offspring (F2), providing evidence of transgenerational effects in amphibians. The adult F2 males demonstrated increased weight and fat body palmitoleic-to-palmitic acid ratio, and decreased plasma glucose levels. The study provides important cross-species evidence of paternal epigenetic inheritance and pollutant-induced transgenerational toxicity, supporting a causal and complex role of environmental contamination in the ongoing species extinctions, particularly of amphibians.

Who's afraid of epigenetics? Habits, instincts, and Charles Darwin\u2019s evolutionary theory

Our paper aims at bringing to the fore the crucial role that habits play in Charles Darwin’s theory of evolution by means of natural selection. We have organized the paper in two steps: first, we analyse value and functions of the concept of habit in Darwin's early works, notably in his Notebooks, and compare these views to his mature understanding of the concept in the Origin of Species and later works; second, we discuss Darwin’s ideas on habits in the light of today’s theories of epigenetic inheritance, which describe the way in which the functioning and expression of genes is modified by the environment, and how these modifications are transmitted over generations. We argue that Darwin’s lasting and multifaceted interest in the notion of habit, throughout his intellectual life, is both conceptually and methodologically relevant. From a conceptual point of view, intriguing similarities can be found between Darwin’s (early) conception of habit and contemporary views on epigenetic inheritance. From a methodological point of view, we suggest that Darwin’s plastic approach to habits, from his early writings up to the mature works, can provide today’s evolutionary scientists with a viable methodological model to address the challenging task of extending and expanding evolutionary theory, with particular reference to the integration of epigenetic mechanisms into existing models of evolutionary change. Over his entire life Darwin has modified and reassessed his views on habits as many times as required by evidence: his work on this notion may represent the paradigm of a habit of good scientific research methodology.

Gametes deficient for Pot1 telomere binding proteins alter levels of telomeric foci for multiple generations

Deficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance. C. elegans Protection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes from pot-2 mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes from pot-1 mutants or pot-1; pot-2 double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose that C. elegans POT-1 may interact with H3K9 methyltransferases during pot-2 mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci.

PiRNAs Coordinate Poly(UG) Tailing to Prevent Aberrant and Permanent Gene Silencing

Noncoding RNAs have emerged as mediators of transgenerational epigenetic inheritance (TEI) in a number of organisms. A robust example of RNA-directed TEI is the inheritance of gene silencing states following RNA interference (RNAi) in the metazoan C. elegans. During RNAi inheritance, gene silencing is transmitted by a self-perpetuating cascade of siRNA-directed poly(UG) tailing of mRNA fragments (pUGylation), followed by siRNA synthesis from poly(UG)-tailed mRNA templates (termed pUG RNA/siRNA cycling). Despite the self-perpetuating nature of pUG RNA/siRNA cycling, RNAi inheritance is finite, suggesting that systems likely exist to prevent permanent RNAi-triggered gene silencing. Here we show that, in the absence of Piwi-interacting RNAs (piRNAs), an animal-specific class of small noncoding RNA, RNAi-based gene silencing can become essentially permanent, lasting at near 100% penetrance for more than five years and hundreds of generations. This permanent gene silencing is mediated by perpetual activation of the pUG RNA/siRNA TEI pathway. Further, we find that piRNAs coordinate endogenous RNAi pathways to prevent germline-expressed genes, which are not normally subjected to TEI, from entering a state of permanent and irreversible epigenetic silencing also mediated by perpetual activation of pUG RNA/siRNA cycling. Together, our results show that one function of C. elegans piRNAs is to insulate germline-expressed genes from aberrant and runaway inactivation by the pUG RNA/siRNA epigenetic inheritance system.

Resveratrol Supplementation Attenuates Cognitive and Molecular Alterations under Maternal High-Fat Diet Intake: Epigenetic Inheritance over Generations.

Environmental factors such as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. Epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol (RSV) HFD + RSV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RSV groups and their offspring. Molecularly, a significant increase in DNA methylation (5-mC) levels, as well as increased gene expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a in HFD + RSV F1 group, were found. Furthermore, a significant increase of N6-Methyladenosine methylation (m6A) levels in HFD+RSV F1, as well as changes in gene expression of its enzymes Methyltransferase like 3 (Mettl3) and FTO alpha-ketoglutarate dependent dioxygenase (Fto) were found. Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as Interleukin 1β (Il1-β), Interleukin 6 (Il-6), Tumor necrosis factor-α (Tnf-α), C-X-C motif chemokine ligand 10 (Cxcl-10), the pro-inflammatory factors monocyte chemoattractant protein 1 (Mcp-1) and Tumor growth factor-β1 (Tgf-β1) in HFD+RSV and HFD+RSV F1 groups. Moreover, there was increased gene expression of neurotrophins such as Neural growth factor (Ngf), Neurotrophin-3 (Nt3), and its receptors Tropomyosin receptor kinase TrkA and TrkB. Likewise, an increase in protein levels of brain-derived neurotrophic factor (BDNF) and phospho-protein kinase B (p-Akt) in HFD+RSV F1 was found. These results suggest that maternal RSV supplementation under HFD intake prevents cognitive decline in senescence-accelerated mice prone 8 (SAMP8) adult offspring, promoting a reduction in triglycerides and leptin plasma levels, changes in the pro-inflammatory profile, and restoring the epigenetic landscape as well as synaptic plasticity.

Specification and epigenomic resetting of the pig germline exhibit conservation with the human lineage

SummaryInvestigations of the human germline and programming are challenging because of limited access to embryonic material. However, the pig as a model may provide insights into transcriptional network and epigenetic reprogramming applicable to both species. Here we show that, during the pre- and early migratory stages, pig primordial germ cells (PGCs) initiate large-scale epigenomic reprogramming, including DNA demethylation involving TET-mediated hydroxylation and, potentially, base excision repair (BER). There is also macroH2A1 depletion and increased H3K27me3 as well as X chromosome reactivation (XCR) in females. Concomitantly, there is dampening of glycolytic metabolism genes and re-expression of some pluripotency genes like those in preimplantation embryos. We identified evolutionarily young transposable elements and gene coding regions resistant to DNA demethylation in acutely hypomethylated gonadal PGCs, with potential for transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute significantly to advances in human germline biology, including in vitro gametogenesis.

Breaking Symmetry: The Asymmetries in Epigenetic Inheritance.

Symmetry and asymmetry are fundamental aspects of life. Most cells within a multicellular organism contain the same genetic information, passed on from one originating cell - the zygote; however, these cells can take on a variety of different identities, with diverse appearances and functions. A fundamental question in biology ponders how cells containing identical DNA content can take on different cell identities. Epigenetic mechanisms could be the symmetry breaking factor, as they are able to change gene expression in cells without changing the DNA sequence. While the process of duplication and segregation of DNA during cell division has been well studied, it is less understood how the epigenetic information is established and inherited in the cells within a multicellular organism. Studies of asymmetric stem cell division, where a stem cell division gives rise to a self-renewed stem cell and a differentiating daughter cell, provides a model to study how epigenetic information is maintained or changed to produce daughter cells with identical genetic information but distinct cell fates. Here, we discuss findings and ideas of how epigenetic information is maintained or changed during asymmetric cell division and the importance of this asymmetry in influencing cell fate.

Long noncoding RNA: A resident staff of genomic instability regulation in tumorigenesis.

Genomic instability is an important characteristic of cancer, which promotes clonal evolution and tumorigenesis by increasing the frequency of gene destruction and loss of genome integrity. Generally, the maintenance of genomic stability depends significantly on the accurate regulation and timely repair of different genomic scales, ranging from DNA sequence to chromatin higher-order structures to chromosomes. Once irreversible damage and imperfect repair occurred, the resulting genomic instability can lead to a higher risk of tumorigenesis. However, how these factors disrupt genomic stability and their specific tumorigenic mechanisms remain unclear. Inspiringly, numerous studies have confirmed that long noncoding RNAs (lncRNAs), an important regulator of epigenetic inheritance, are functional in such process. Thus, this review aimed to discuss the vital factors that may lead to genomic instability at these multiple genomic scales, with an emphasis on the role of lncRNAs in it.

Parental nucleosome segregation and the inheritance of cellular identity.

Gene expression programmes conferring cellular identity are achieved through the organization of chromatin structures that either facilitate or impede transcription. Among the key determinants of chromatin organization are the histone modifications that correlate with a given transcriptional status and chromatin state. Until recently, the details for the segregation of nucleosomes on DNA replication and their implications in re-establishing heritable chromatin domains remained unclear. Here, we review recent findings detailing the local segregation of parental nucleosomes and highlight important advances as to how histone methyltransferases associated with the establishment of repressive chromatin domains facilitate epigenetic inheritance.

The current perspective on genetic and epigenetic factors in sperm maturation in the epididymis.

Male infertility affects approximately 30% of infertile couples. As spermatozoa mature in the epididymal lumen, their potential for mobility increases, and their protein, lipid and small RNA (sRNA) content changes, whereas capacitation and fertilisation take place in the female reproductive tract. Both of the latter processes are affected by maturation, because impaired maturation causes premature capacitation and fertilization. The epididymis produces a suitable environment for sperm maturation via ion transport, vesicle secretion and protein matrix formation. The microenvironment for sperm maturation varies in three broad segments: the caput, the corpus and the cauda epididymis. Epididymosomes transfer proteins, lipids and sRNAs from the epididymal epithelium to spermatozoa and genetic alterations of epididymal genes can lead to decreased sperm motility, morphological abnormalities of spermatozoa and subfertility. Genetic factors are involved in all aetiological categories in male infertility. However, studies conducted on the genes involved in epididymal functions are limited. The sRNA content of spermatozoa changes during epididymal migration, and these sRNAs play a role in embryo development and epigenetic inheritance. This review aims to clarify the role of the epididymal epithelium in the maturation of spermatozoa in light of the current molecular genomic knowledge.

Replication-Coupled Chromatin Remodeling: An Overview of Disassembly and Assembly of Chromatin during Replication.

The doubling of genomic DNA during the S-phase of the cell cycle involves the global remodeling of chromatin at replication forks. The present review focuses on the eviction of nucleosomes in front of the replication forks to facilitate the passage of replication machinery and the mechanism of replication-coupled chromatin assembly behind the replication forks. The recycling of parental histones as well as the nuclear import and the assembly of newly synthesized histones are also discussed with regard to the epigenetic inheritance.

Generational Effects of Opioid Exposure.

Definition:The inheritance of substance abuse, including opioid abuse, may be influenced by genetic and non-genetic factors related to the environment, such as stress and socioeconomic status. These non-genetic influences on the heritability of a trait can be attributed to epigenetics. Epigenetic inheritance can result from modifications passed down from the mother, father, or both, resulting in either maternal, paternal, or parental epigenetic inheritance, respectively. These epigenetic modifications can be passed to the offspring to result in multigenerational, intergenerational, or transgenerational inheritance. Human and animal models of opioid exposure have shown generational effects that result in molecular, developmental, and behavioral alterations in future generations.

Integration of sperm ncRNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance

BackgroundEnvironmentally induced epigenetic transgenerational inheritance of pathology and phenotypic variation has been demonstrated in all organisms investigated from plants to humans. This non-genetic form of inheritance is mediated through epigenetic alterations in the sperm and/or egg to subsequent generations. Although the combined regulation of differential DNA methylated regions (DMR), non-coding RNA (ncRNA), and differential histone retention (DHR) have been shown to occur, the integration of these different epigenetic processes remains to be elucidated. The current study was designed to examine the integration of the different epigenetic processes.ResultsA rat model of transiently exposed F0 generation gestating females to the agricultural fungicide vinclozolin or pesticide DDT (dichloro-diphenyl-trichloroethane) was used to acquire the sperm from adult males in the subsequent F1 generation offspring, F2 generation grand offspring, and F3 generation great-grand offspring. The F1 generation sperm ncRNA had substantial overlap with the F1, F2 and F3 generation DMRs, suggesting a potential role for RNA-directed DNA methylation. The DMRs also had significant overlap with the DHRs, suggesting potential DNA methylation-directed histone retention. In addition, a high percentage of DMRs induced in the F1 generation sperm were maintained in subsequent generations.ConclusionsMany of the DMRs, ncRNA, and DHRs were colocalized to the same chromosomal location regions. Observations suggest an integration of DMRs, ncRNA, and DHRs in part involve RNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance.

Epigenetic Memories: The Hidden Drivers of Bacterial Persistence?

Epigenetic modifications, including DNA methylation, stably alter gene expression without modifying genomic sequences. Recent evidence suggests that epigenetic regulation coupled with a long-term 'memory' effect plays a major role within bacterial persistence formation. Today, emerging high-resolution, single-molecule sequencing technologies allow an increased focus on DNA modifications as regulatory epigenetic marks, which presents a unique opportunity to identify possible epigenetic drivers of bacterial persistence.

Environmental impacts on sperm and oocyte epigenetics affect embryo cell epigenetics and transcription to promote the epigenetic inheritance of pathology and phenotypic variation.

Previous studies have demonstrated that exposure to environmental factors can cause epigenetic modifications to germ cells, particularly sperm, to promote epigenetic and transcriptome changes in the embryo. These germ cell and embryo cell epigenetic alterations are associated with phenotypic changes in offspring. Epigenetic inheritance requires epigenetic changes (i.e. epimutations) in germ cells that promote epigenetic and gene expression changes in embryos. The objective of this perspective is to examine the evidence that germ cell epigenome modifications are associated with embryo cell epigenetic and transcriptome changes that affect the subsequent development of all developing somatic cells to promote phenotype change. Various epigenetic changes in sperm, including changes to histone methylation, histone retention, non-coding RNA expression and DNA methylation, have been associated with alterations in embryo cell epigenetics and gene expression. Few studies have investigated this link for oocytes. The studies reviewed herein support the idea that environmentally induced epigenetic changes in germ cells affect alterations in embryo cell epigenetics and transcriptomes that have an important role in the epigenetic inheritance of pathology and phenotypic change.

Transgenerational Epigenetic Inheritance of Alzheimer's Disease Mediated by Acetyltransferase MYS-2/MOF

Transgenerational Epigenetic Inheritance of Alzheimer's Disease Mediated by Acetyltransferase MYS-2/MOF