Carriers Of Epigenetic Information Research Articles

Insight into noncanonical small noncoding RNAs in Influenza A virus infection

Influenza A virus (IAV) induces acute respiratory infections in birds and various mammals, including humans, and presents a significant global public health concern, with considerable economic consequences. Recently, researchers have shown keen interest in noncanonical small noncoding RNAs (sncRNAs) as carriers of epigenetic information, including tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNA (rsRNAs), and Y RNA-derived small RNAs (ysRNAs). Particularly, tsRNAs and rsRNAs are detected in diverse species and demonstrate evolutionary conservation. We analyzed sncRNAs sequencing data in the pulmonary tissue of two genetically distinct mouse strains, C57BL/6J and DBA/2J, to explore strain-specific variations of sncRNAs in response to IAV infection. We systematically compiled information on noncanonical sncRNAs in these two strains and investigated the tsRNAs/rsRNAs/ysRNAs profiles influenced by IAV infection. Specifically, four noncanonical sncRNA families, including rsRNA-12S, GtsRNA-Arg-CCT, GtsRNA-Arg-TCT, and GtsRNA-Lys-TTT, exhibited upregulation upon IAV infection. Notably, DBA/2J mice showed earlier systemic differential expression of noncanonical sncRNAs after IAV infection compared to C57BL/6J mice. Additionally, our study revealed a strain-specific biogenesis of MtsRNAs in response to IAV infection. Also, distinct co-expression patterns of MtsRNAs were observed between C57BL/6J and DBA/2J mice, with DBA/2J mice showing broader positive co-expression of MtsRNAs with various sncRNA families compared to C57BL/6J mice. Our study provides a novel insight into noncanonical sncRNAs and their implications in IAV pathology and mouse strain specificity.

Histone deficiency and hypoacetylation in the aging retinal pigment epithelium.

Histones serve as a major carrier of epigenetic information in the form of post-translational modifications which are vital for controlling gene expression, maintaining cell identity, and ensuring proper cellular function. Loss of histones in the aging genome can drastically impact the epigenetic landscape of the cell leading to altered chromatin structure and changes in gene expression profiles. In this study, we investigated the impact of age-related changes on histone levels and histone acetylation in the retinal pigment epithelium (RPE) and retina of mice. We observed a global reduction of histones H1, H2A, H2B, H3, and H4 in aged RPE/choroid but not in the neural retina. Transcriptomic analyses revealed significant downregulation of histones in aged RPE/choroid including crucial elements of the histone locus body (HLB) complex involved in histone pre-mRNA processing. Knockdown of HINFP, a key HLB component, in human RPE cells induced histone loss, senescence, and the upregulation of senescence-associated secretory phenotype (SASP) markers. Replicative senescence and chronological aging in human RPE cells similarly resulted in progressive histone loss and acquisition of the SASP. Immunostaining of human retina sections revealed histone loss in RPE with age. Acetyl-histone profiling in aged mouse RPE/choroid revealed a specific molecular signature with loss of global acetyl-histone levels, including H3K14ac, H3K56ac, and H4K16ac marks. These findings strongly demonstrate histone loss as a unique feature of RPE aging and provide critical insights into the potential mechanisms linking histone dynamics, cellular senescence, and aging.

Studying histone inheritance in different systems using imaging-based methods and perspectives.

Understanding cell identity is critically important in the fields of cell and developmental biology. During cell division, a mother cell duplicates the genetic material and cellular components to give rise to two daughter cells. While both cells receive the same genetic information, they can take on similar or different cell fates, resulting from a symmetric or asymmetric division. These fates can be modulated by epigenetic mechanisms that can alter gene expression without changing genetic information. Histone proteins, which wrap DNA into fundamental units of chromatin, are major carriers of epigenetic information and can directly influence gene expression and other cellular functions through their interactions with DNA. While it has been well studied how the genetic information is duplicated and segregated, how epigenetic information, such as histones, are inherited through cell division is still an area of investigation. Since canonical histone proteins are incorporated into chromatin during DNA replication and can be modified over time, it is important to study their inheritance within the context of the cell cycle. Here, we outline the biological basis of histone inheritance as well as the imaging-based experimental design that can be used to study this process. Furthermore, we discuss various studies that have investigated this phenomenon with the focus on asymmetrically dividing cells in different systems. This synopsis provides insight into histone inheritance within the context of the cell cycle, along with the technical methods and considerations that must be taken when studying this process in vivo.

SMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters

Histone marks, carriers of epigenetic information, regulate gene expression. In mammalian cells, H3K36me3 is mainly catalyzed by SETD2 at gene body regions. Here, we find that in addition to gene body regions, H3K36me3 is enriched at promoters in primary cells. Through screening, we identify SMYD5, which is recruited to chromatin by RNA polymerase II, as a methyltransferase catalyzing H3K36me3 at promoters. The enzymatic activity of SMYD5 is dependent on its C-terminal glutamic acid-rich domain. Overexpression of full-length Smyd5, but not the C-terminal domain-truncated Smyd5, restores H3K36me3 at promoters in Smyd5 knockout cells. Furthermore, elevated Smyd5 expression contributes to tumorigenesis in liver hepatocellular carcinoma. Together, our findings identify SMYD5 as the H3K36me3 methyltransferase at promoters that regulates gene expression, providing insights into the localization and function of H3K36me3.

The Transmission of Intergenerational Epigenetic Information by Sperm microRNAs.

Epigenetic information is transmitted from one generation to the next, modulating the phenotype of offspring non-genetically in organisms ranging from plants to mammals. For intergenerational non-genetic inheritance to occur, epigenetic information must accumulate in germ cells. The three main carriers of epigenetic information—histone post-translational modifications, DNA modifications, and RNAs—all exhibit dynamic patterns of regulation during germ cell development. For example, histone modifications and DNA methylation are extensively reprogrammed and often eliminated during germ cell maturation and after fertilization during embryogenesis. Consequently, much attention has been given to RNAs, specifically small regulatory RNAs, as carriers of inherited epigenetic information. In this review, we discuss examples in which microRNAs have been implicated as key players in transmitting paternal epigenetic information intergenerationally.

Biophysics of Chromatin Remodeling.

As primary carriers of epigenetic information and gatekeepers of genomic DNA, nucleosomes are essential for proper growth and development of all eukaryotic cells. Although they are intrinsically dynamic, nucleosomes are actively reorganized by ATP-dependent chromatin remodelers. Chromatin remodelers contain helicase-like ATPase motor domains that can translocate along DNA, and a long-standing question in the field is how this activity is used to reposition or slide nucleosomes. In addition to ratcheting along DNA like their helicase ancestors, remodeler ATPases appear to dictate specific alternating geometries of the DNA duplex, providing an unexpected means for moving DNA past the histone core. Emerging evidence supports twist-based mechanisms for ATP-driven repositioning of nucleosomes along DNA. In this review, we discuss core experimental findings and ideas that have shaped the view of how nucleosome sliding may be achieved.

Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance

BackgroundA growing body of evidence suggests that certain epiphenotypes can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization.ResultsBy integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNA-seq data collected during multiple stages of primordial germ cell and pre-implantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global de-methylation, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germline and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global de-methylation, become de-methylated during global de-methylation, and then become re-methylated.ConclusionsThe results suggest that transcription factors can act as carriers of epigenetic information during germ cell and pre-implantation development by ensuring that the methylation status of CpGs is maintained. These findings provide the basis for a mechanistic description of trans-generational inheritance of epigenetic information in mammals.

Mature sperm small-RNA profile in the sparrow: implications for transgenerational effects of age on fitness.

Mammalian sperm RNA has recently received a lot of interest due to its involvement in epigenetic germline inheritance. Studies of epigenetic germline inheritance have shown that environmental exposures can induce effects in the offspring without altering the DNA sequence of germ cells. Most mechanistic studies were conducted in laboratory rodents and C.elegans while observational studies confirm the phenotypic phenomenon in wild populations of humans and other species including birds. Prominently, paternal age in house sparrows affects offspring fitness, yet the mechanism is unknown. This study provides a first reference of house sparrow sperm small RNA as an attempt to uncover their role in the transmission of the effects of paternal age on the offspring. In this small-scale pilot, we found no statistically significant differences between miRNA and tRNA fragments in aged and prime sparrow sperm. These results indicate a role of other epigenetic information carriers, such as distinct RNA classes, RNA modifications, DNA methylation and retained histones, and a clear necessity of future studies in wild populations.

Intricate regulation on epigenetic stability of the subtelomeric heterochromatin and the centromeric chromatin in fission yeast.

In eukaryotes, the integrity of chromatin structure and organization is crucial to diverse key cellular processes from development to disease avoidance. To maintain the cell identity through mitotic cell generations, the genome (the genomic DNA sequence) as well as the epigenome (pertaining various forms of epigenetic information carriers, such as histone modifications, nucleosome positioning and the chromatin organization) is inherited with high fidelity. In comparison to the wealth of knowledge on genetic stability, we know much less on what may control the accuracy of epigenetic inheritance. In our recent work in the fission yeast Schizosaccharomyces pombe, by quantifying the epigenetic fidelity of CENP-A/Cnp1 or H3K9me2 nucleosome inheritance through cell divisions, we demonstrated that Ccp1, a homolog of histone chaperone Vps75 in budding yeast, participates in the modulation of centromeric nucleosomal epigenetic stability as well as proper heterochromatin organization. In this essay, we focus on discussing the uniquely high dynamicity of the subtelomeric heterochromatin regions and the complex mechanisms regulating epigenetic stability of centromeric chromatin.

Extracellular Vesicle-Associated RNA as a Carrier of Epigenetic Information.

Post-transcriptional regulation of messenger RNA (mRNA) metabolism and subcellular localization is of the utmost importance both during development and in cell differentiation. Besides carrying genetic information, mRNAs contain cis-acting signals (zip codes), usually present in their 5′- and 3′-untranslated regions (UTRs). By binding to these signals, trans-acting factors, such as RNA-binding proteins (RBPs), and/or non-coding RNAs (ncRNAs), control mRNA localization, translation and stability. RBPs can also form complexes with non-coding RNAs of different sizes. The release of extracellular vesicles (EVs) is a conserved process that allows both normal and cancer cells to horizontally transfer molecules, and hence properties, to neighboring cells. By interacting with proteins that are specifically sorted to EVs, mRNAs as well as ncRNAs can be transferred from cell to cell. In this review, we discuss the mechanisms underlying the sorting to EVs of different classes of molecules, as well as the role of extracellular RNAs and the associated proteins in altering gene expression in the recipient cells. Importantly, if, on the one hand, RBPs play a critical role in transferring RNAs through EVs, RNA itself could, on the other hand, function as a carrier to transfer proteins (i.e., chromatin modifiers, and transcription factors) that, once transferred, can alter the cell’s epigenome.

Effects of a parental exposure to diuron on Pacific oyster spat methylome.

Environmental epigenetic is an emerging field that studies the cause–effect relationship between environmental factors and heritable trait via an alteration in epigenetic marks. This field has received much attentions since the impact of environmental factors on different epigenetic marks have been shown to be associated with a broad range of phenotypic disorders in natural ecosystems. Chemical pollutants have been shown to affect immediate epigenetic information carriers of several aquatic species but the heritability of the chromatin marks and the consequences for long term adaptation remain open questions. In this work, we investigated the impact of the diuron herbicide on the DNA methylation pattern of spat from exposed Crassotrea gigas genitors. This oyster is one of the most important mollusk species produced worldwide and a key coastal economic resource in France. The whole genome bisulfite sequencing (WGBS, BS-Seq) was applied to obtain a methylome at single nucleotide resolution on DNA extracted from spat issued from diuron exposed genitors comparatively to control spat. We showed that the parental diuron exposure has an impact on the DNA methylation pattern of its progeny. Most of the differentially methylated regions occurred within coding sequences and we showed that this change in methylation level correlates with RNA level only in a very small group of genes. Although the DNA methylation profile is variable between individuals, we showed conserved DNA methylation patterns in response to parental diuron exposure. This relevant result opens perspectives for the setting of new markers based on epimutations as early indicators of marine pollutions.

Sperm tsRNAs and acquired metabolic disorders.

Many findings support the hypothesis that metabolic changes associated with environmental factors can be transmitted from father to offspring. The molecular mechanisms underlying the intergenerational transmission of metabolic changes remain to be fully explored. These acquired metabolic disorders in offspring may be partially explained by some potential epigenetic information carriers such as DNA methylation, histone modification and small non-coding RNAs. Recent evidence shows that sperm tRNA-derived small RNAs (tsRNAs) as a type of paternal epigenetic information carrier may mediate intergenerational inheritance. In this review, we provide current knowledge of a father's influence on metabolic disorders in subsequent generations and discuss the roles of sperm tsRNAs and their modifications in paternal epigenetic information transmission.

Intergenerational Transfer of Epigenetic Information in Sperm.

The inheritance of information beyond DNA sequence, known as epigenetic inheritance, has been implicated in a multitude of biological processes from control of plant flowering time to cancer in humans. In addition to epigenetic inheritance that occurs in dividing cells of a multicellular organism, it is also increasingly clear that at least some epigenetic information is transmitted via the gametes in a multitude of organisms, including mammals. Here, I review the evidence for epigenetic information carriers in mammalian sperm, and explore the emerging field of intergenerational transfer of environmental information.

Nucleation: The Birth of a New Protein Phase

Nucleation is a process that initiates phase transitions. Since the classical work of Gibbs on nucleation thermodynamics at the end of the nineteenth century, research into nucleation processes has been spread into a huge variety of scientific fields. To date, nucleation has been studied in disciplines ranging from biophysics to cosmology in systems spanning atomic to planetary scales and beyond (1). Proteins in solution are also known historically to form a variety of states and structures through nucleation (2,3).

Vererbung von Merkmalen außerhalb der primären Sequenz der DNA

Epigenetics is the mitotic or meiotic inheritance of acquired traits that are not encoded in the primary DNA sequence. On a molecular level, the epigenetic code is programmed as chemical modifications of the genomic DNA or of DNA-associated histone proteins. More recently, certain RNA species were identified as additional carriers of epigenetic information. Epigenetic programming is essential for most biological processes and links environmental factors to gene expression.

Environmental epigenetic inheritance through gametes and implications for human reproduction.

Traditional studies focused on DNA as the heritable information carrier that passes the phenotype from parents to offspring. However, increasing evidence suggests that information, that is independent of the DNA sequence, termed epigenetic information, can be inherited between generations. Recently, in our lab, we found that prediabetes in fathers increases the susceptibility to diabetes in offspring through gametic cytosine methylation changes. Paternal prediabetes changed overall methylation patterns in sperm, and a large portion of differentially methylated loci can be transmitted to pancreatic islets of offspring up to the second generation. In this review, we survey the extensive examples of environmentally induced epigenetic inheritance in various species, ranging from Caenorhabditis elegans to humans. We focus mainly on elucidating the molecular basis of environmental epigenetic inheritance through gametes, which is an emerging theme and has important implications for explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases, which is also important for understanding the influence of environmental exposures on reproductive and overall health in offspring. For this review, we included relevant data and information obtained through a PubMed database search for all English language articles published up to August 2014 which included the term 'environmental epigenetic inheritance' and 'transgenerational epigenetic inheritance'. We focused on research papers using animal models including Drosophila, C. elegans, mouse and rat. Human data were also included. Evidence from animal models suggests that environmental epigenetic inheritance through gametes exists in various species. Extensive molecular evidence suggests that epigenetic information carriers including DNA methylation, non-coding RNAs and chromatin proteins in gametes play important roles in the transmission of phenotypes from parents to offspring. Given the large number of experimental evidence from various organisms, it is clear that parental environmental alterations can affect the phenotypes of offspring through gametic epigenetic alterations. This more recent thinking based on new data may have implications in explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases. This also implies that, in the near future, epigenetic factors which are heritable should be regarded important in determining the risk of certain diseases. Moreover, identification of epigenetic markers in gametes (polar body or sperm) may hold great promise for predicting susceptibility to and preventing certain non-genetic diseases in offspring, as well as providing indications on parental environmental exposures.

The evolution of epigenetics.

Early studies of the developing embryo raised the question of how a fertilized egg could give rise to a complex multicellular organism containing many different kinds of cells. The term epigenetics originally referred to the study of these processes. With the advent of detailed knowledge of mechanisms of gene expression, this definition was superseded by another: epigenetics concerned the transmission of phenotype through mitosis or the germ line by mechanisms that did not involve changes in the DNA sequence. Much effort has been spent in attempting to identify and characterize these events. Work initially focused on DNA methylation as an epigenetic mark, but more recently there has been an emphasis on histone modifications as possible carriers of epigenetic information. However, there is confusion between situations in which the modifications may be propagated through cell division, thus helping to maintain a pattern of gene expression, and situations in which the modifications are simply part of the transcriptional apparatus. Arguments about the role of the histones have led to a reexamination of the definition of epigenetics and the primary events in development leading to cell type specific gene expression patterns.

Histone modifications and a choice of variant: a language that helps the genome express itself.

Covalent post-translational modifications on histones impact chromatin structure and function. Their misfunction, along with perturbations or mutations in genes that regulate their dynamic status, has been observed in several diseases. Thus, targeting histone modifications represents attractive opportunities for therapeutic intervention and biomarker discovery. The best approach to address this challenge is to paint a comprehensive picture integrating the growing number of modifications on individual residues and their combinatorial association, the corresponding modifying enzymes, and effector proteins that bind modifications. Furthermore, how they are imposed in a distinct manner during the cell cycle and on specific histone variants are important dimensions to consider. Firstly, this report highlights innovative technologies used to characterize histone modifications, and the corresponding enzymes and effector proteins. Secondly, we examine the recent progress made in understanding the dynamics and maintenance of histone modifications on distinct variants. We also discuss their roles as potential carriers of epigenetic information. Finally, we provide examples of initiatives to exploit histone modifications in cancer management, with the potential for new therapeutic opportunities.

Elucidating the molecular bases of epigenetic inheritance in non-model invertebrates: the case of the root-knot nematode Meloidogyne incognita.

Root-knot nematodes of the genus Meloidogyne are biotrophic plant parasites that exhibit different life cycles and reproduction modes, ranging from classical amphimixis to obligatory mitotic parthenogenesis (apomixis), depending on the species. Meloidogyne incognita, an apomictic species, exhibits a worldwide distribution and a wide host range affecting more than 3000 plant species. Furthermore, evidences suggest that apomixis does not prevent M. incognita from adapting to its environment in contrast to what is expected from mitotic parthenogenesis that should theoretically produce clonal progenies. This raises questions about mechanisms of genome plasticity leading to genetic variation and adaptive evolution in apomictic animals. We reasoned that epigenetic mechanisms might in part be responsible for the generation of phenotypic variants that provide potential for rapid adaptation. We established therefore a pipeline to investigate the principal carriers of epigenetic information, DNA methylation and post-translational histone modifications. Even if M. incognita possesses the epigenetic machinery i.e., chromatin modifying enzymes, 5-methyl-cytosine and 5-hydroxy-methyl-cytosine content is absent or very weak. In contrast, we demonstrated that the canonical histone modifications are present and chromatin shows typical nucleosome structure. This work is the first characterization of carriers of epigenetic information in M. incognita and constitutes a preamble to further investigate if M. incognita development and its adaptation to plant hosts are under epigenetic control. Our pipeline should allow performing similar types of studies in any non-model organism.

5-methyl-cytosine and 5-hydroxy-methyl-cytosine in the genome of Biomphalaria glabrata, a snail intermediate host of Schistosoma mansoni

BackgroundBiomphalaria glabrata is the mollusc intermediate host for Schistosoma mansoni, a digenean flatworm parasite that causes human intestinal schistosomiasis. An estimated 200 million people in 74 countries suffer from schistosomiasis, in terms of morbidity this is the most severe tropical disease after malaria. Epigenetic information informs on the status of gene activity that is heritable, for which changes are reversible and that is not based on the DNA sequence. Epigenetic mechanisms generate variability that provides a source for potentially heritable phenotypic variation and therefore could be involved in the adaptation to environmental constraint. Phenotypic variations are particularly important in host-parasite interactions in which both selective pressure and rate of evolution are high. In this context, epigenetic changes are expected to be major drivers of phenotypic plasticity and co-adaptation between host and parasite. Consequently, with characterization of the genomes of invertebrates that are parasite vectors or intermediate hosts, it is also essential to understand how the epigenetic machinery functions to better decipher the interplay between host and parasite.MethodsThe CpGo/e ratios were used as a proxy to investigate the occurrence of CpG methylation in B. glabrata coding regions. The presence of DNA methylation in B. glabrata was also confirmed by several experimental approaches: restriction enzymatic digestion with isoschizomers, bisulfite conversion based techniques and LC-MS/MS analysis.ResultsIn this work, we report that DNA methylation, which is one of the carriers of epigenetic information, occurs in B. glabrata; approximately 2% of cytosine nucleotides are methylated. We describe the methylation machinery of B. glabrata. Methylation occurs predominantly at CpG sites, present at high ratios in coding regions of genes associated with housekeeping functions. We also demonstrate by bisulfite treatment that methylation occurs in multiple copies of Nimbus, a transposable element.ConclusionsThis study details DNA methylation for the first time, one of the carriers of epigenetic information in B. glabrata. The general characteristics of DNA methylation that we observed in the B. glabrata genome conform to what epigenetic studies have reported from other invertebrate species.