Oxygen-reactive species and antioxidant responses during development: the metabolic paradox of cellular differentiation

Metabolic gradients are established during early phases of development and their existence influences subsequent developmental events. Variations in oxygen supply and oxygen metabolism associated with the gradation of metabolic rate in embryos appear to form one basis for the influence of metabolic gradients on development. The rate of oxygen metabolism affects the rate of oxidant generation by various cellular biochemical pathways. Cells contain antioxidant defenses that respond to variations in cellular oxidant production. Large changes in the activity of the antioxidant enzyme superoxide dismutase and changes in cellular redox state occur during the differentiation of many types of cells. These changes correspond to an increased rate of oxidant production; the cellular environment becomes more prooxidizing during differentiation. Evidence is presented that implicates oxidants as a factor that can stimulate alterations in gene expression. Possible mechanisms by which oxidants influence gene expression are also discussed.     

Epigenetics in cardiac development,function, and disease

Substantial new knowledge has accrued, over the past few years, concerning the epigenetic regulation of heart development and disease. Epigenetic mechanisms comprise DNA methylation, ATP-dependent chromatin remodeling, histone modifications, and non-coding RNAs. Many of these processes have been ascertained to influence the tight spatiotemporal control of gene expression during cardiac development. Nevertheless, the relative contribution of each mechanism and their potentially complex interplay remain largely unexplored. Cardiac development and disease are linked through the reactivation of fetal genes upon cardiac hypertrophy and failure. In cardiac disease, changes in gene expression are accompanied and influenced by distinct changes in histone modifications. Detailed knowledge about the epigenetic pathways of cardiac development and function is expected ultimately to lead to novel therapeutic strategies for heart disease and regenerative medicine.     

Sensing cellular states—signaling to chromatin pathways targeting Polycomb and Trithorax group function

Cells respond to extra- and intra-cellular signals by dynamically changing their gene expression patterns. After termination of the original signal, new expression patterns are maintained by epigenetic DNA and histone modifications. This represents a powerful mechanism that enables long-term phenotypic adaptation to transient signals. Adaptation of epigenetic landscapes is important for mediating cellular differentiation during development and allows adjustment to altered environmental conditions throughout life. Work over the last decade has begun to elucidate the way that extra- and intra-cellular signals lead to changes in gene expression patterns by directly modulating the function of chromatin-associated proteins. Here, we review key signaling-to-chromatin pathways that are specifically thought to target Polycomb and Trithorax group complexes, a classic example of epigenetically acting gene silencers and activators important in development, stem cell differentiation and cancer. We discuss the influence that signals triggered by kinase cascades, metabolic fluctuations and cell-cycle dynamics have on the function of these protein complexes. Further investigation into these pathways will be important for understanding the mechanisms that maintain epigenetic stability and those that promote epigenetic plasticity.     

Oxygen tension affects histone remodeling of in vitro–produced embryos in a bovine model

In vitro production of bovine embryos is a biotechnology of great economic impact. Epigenetic processes, such as histone remodeling, control gene expression and are essential for proper embryo development. Given the importance of IVP as a reproductive biotechnology, the role of epigenetic processes during embryo development, and the important correlation between culture conditions and epigenetic patterns, the present study was designed as a 2 × 2 factorial to investigate the influence of varying oxygen tensions (O₂; 5% and 20%) and concentrations of fetal bovine serum (0% and 2.5%), during IVC, in the epigenetic remodeling of H3K9me2 (repressive) and H3K4me2 (permissive) in bovine embryos. Bovine oocytes were used for IVP of embryos, cleavage and blastocyst rates were evaluated, and expanded blastocysts were used for evaluation of the histone marks H3K9me2 and H3K4me2. Morulae and expanded blastocysts were also used to evaluate the expression of remodeling enzymes, specific to the aforementioned marks, by real-time polymerase chain reaction. Embryos produced in the presence of fetal bovine serum (2.5%) had a 10% higher rate of blastocyst formation. Global staining for the residues H3K9me2 and H3K4me2 was not affected significantly by the presence of serum. Notwithstanding, the main effect of oxygen tension was significant for both histone marks, with both repressive and permissive marks being higher in embryos cultured at the higher oxygen tension; however, expression of the remodeling enzymes did not differ in morulae or blastocysts in response to the varying oxygen tension. These results suggest that the use of serum during IVC of embryos increases blastocyst rate without affecting the evaluated histone marks and that oxygen tension has an important effect on the histone marks H3K9me2 and H3K4me2 in bovine blastocysts.     

Epigenetics and airways disease

Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.     

Epigenetic gene regulation by plant Jumonji group of histone demethylase

Histone methylation plays an important role in epigenetic regulation of gene expression. Reversible methylation/demethylation of several histone lysine residues is mediated by distinct histone methyltransferases and histone demethylases. Jumonji proteins have been characterized to be involved in histone demethylation. Plant Jumonji homologues are found to have important functions in epigenetic processes, gene expression and plant development and to play an essential role in interplay between histone modifications and DNA methylation. This article is part of a Special Issue entitled: Epigenetic Control of cellular and developmental processes in plants.     

Cooperative DNA and histone binding by Uhrf2 links the two major repressive epigenetic pathways

Gene expression is regulated by DNA as well as histone modifications but the crosstalk and mechanistic link between these epigenetic signals are still poorly understood. Here we investigate the multi-domain protein Uhrf2 that is similar to Uhrf1, an essential cofactor of maintenance DNA methylation. Binding assays demonstrate a cooperative interplay of Uhrf2 domains that induces preference for hemimethylated DNA, the substrate of maintenance methylation, and enhances binding to H3K9me3 heterochromatin marks. FRAP analyses revealed that localization and binding dynamics of Uhrf2 in vivo require an intact tandem Tudor domain and depend on H3K9 trimethylation but not on DNA methylation. Besides the cooperative DNA and histone binding that is characteristic for Uhrf2, we also found an opposite expression pattern of uhrf1 and uhrf2 during differentiation. While uhrf1 is mainly expressed in pluripotent stem cells, uhrf2 is upregulated during differentiation and highly expressed in differentiated mouse tissues. Ectopic expression of Uhrf2 in uhrf1(-/-) embryonic stem cells did not restore DNA methylation at major satellites indicating functional differences. We propose that the cooperative interplay of Uhrf2 domains may contribute to a tighter epigenetic control of gene expression in differentiated cells.     

Chromatin remodeling and human disease

In the past few years, there has been a nascent convergence of scientific understanding of inherited human diseases with epigenetics. Identified epigenetic processes involved in human disease include covalent DNA modifications, covalent histone modifications, and histone relocation. Each of these processes influences chromatin structure and thereby regulates gene expression and DNA methylation, replication, recombination, and repair. The importance of these processes for nearly all aspects of normal growth and development is illustrated by the array of multi-system disorders and neoplasias caused by their dysregulation.     

NATURAL VARIATION IN EPIGENETIC GENE REGULATION AND ITS EFFECTS ON PLANT DEVELOPMENTAL TRAITS

In plants, epigenetic variation contributes to phenotypic differences in developmental traits. At the mechanistic level, this variation is conferred by DNA methylation and histone modifications. We describe several examples in which changes in gene expression caused by variation in DNA methylation lead to alterations in plant development. In these examples, the presence of repeated sequences or transposons within the promoters of the affected genes are associated with DNA methylation and gene inactivation. Small interfering RNAs expressed from these sequences recruit DNA methylation to the gene. Some of these methylated alleles are unstable giving rise to revertant sectors during mitosis and to progeny in which the methylated state is lost. However, others are stable for many generations and persist through speciation. These examples indicate that although DNA methylation influences gene expression, this is frequently dependent on classical changes to DNA sequence such as transposon insertions. By contrast, forms of histone methylation cause repression of gene expression that is stably inherited through mitosis but that can also be erased over time or during meiosis. A striking example involves the induction of flowering by exposure to low winter temperatures in Arabidopsis thaliana and its relatives. Histone methylation participates in repression of expression of an inhibitor of flowering during cold. In annual, semelparous species such as A. thaliana, this histone methylation is stably inherited through mitosis after return from cold to warm temperatures allowing the plant to flower continuously during spring and summer until it senesces. However, in perennial, iteroparous relatives the histone modification rapidly disappears when temperatures rise, allowing expression of the floral inhibitor to increase and limiting flowering to a short interval. In this case, epigenetic histone modifications control a key adaptive trait, and their pattern changes rapidly during evolution associated with life‐history strategy. We discuss these examples of epigenetic developmental traits with emphasis on the underlying mechanisms, their stability, and adaptive value.     

Current advances in epigenetic modification and alteration during mammalian ovarian folliculogenesis

During the growth and development of mammalian ovarian follicles, the activation and deactivation of mass genes are under the synergistic control of diverse modifiers through genetic and epigenetic events. Many factors regulate gene activity and functions through epigenetic modification without altering the DNA sequence, and the common mechanisms may include but are not limited to: DNA methylation, histone modifications (e.g., acetylation, deacetylation, phosphorylation, methylation, and ubiquitination), and RNA-associated silencing of gene expression by noncoding RNA. Over the past decade, substantial progress has been achieved in studies involving the epigenetic alterations during mammalian germ cell development. A number of candidate regulatory factors have been identified. This review focuses on the current available information of epigenetic alterations (e.g., DNA methylation, histone modification, noncoding-RNA-mediated regulation) during mammalian folliculogenesis and recounts when and how epigenetic patterns are differentially established, maintained, or altered in this process. Based on different types of epigenetic regulation, our review follows the temporal progression of events during ovarian folliculogenesis and describes the epigenetic changes and their contributions to germ cell-specific functions at each stage (i.e., primordial folliculogenesis (follicle formation), follicle maturation, and follicular atresia).     

Epigenetic marks in the <Emphasis Type="Italic">Hyacinthus orientalis</Emphasis> L. mature pollen grain and during in vitro pollen tube growth

During the sexual reproduction of flowering plants, epigenetic control of gene expression and genome integrity by DNA methylation and histone modifications plays an important role in male gametogenesis. In this study, we compared the chromatin modification patterns of the generative, sperm cells and vegetative nuclei during Hyacinthus orientalis male gametophyte development. Changes in the spatial and temporal distribution of 5-methylcytosine, acetylated histone H4 and histone deacetylase indicated potential differences in the specific epigenetic state of all analysed cells, in both the mature cellular pollen grains and the in vitro growing pollen tubes. Interestingly, we observed unique localization of chromatin modifications in the area of the generative and the vegetative nuclei located near each other in the male germ unit, indicating the precise mechanisms of gene expression regulation in this region. We discuss the differences in the patterns of the epigenetic marks along with our previous reports of nuclear metabolism and changes in chromatin organization and activity in hyacinth male gametophyte cells. We also propose that this epigenetic status of the analysed nuclei is related to the different acquired fates and biological functions of these cells.     

Dynamics of histone H3 lysine 27 trimethylation in plant development

The development of multicellular organisms is governed partly by temporally and spatially controlled gene expression. DNA methylation, covalent modifications of histones, and the use of histone variants are the major epigenetic mechanisms governing gene expression in plant development. In this review, we zoom in onto histone H3 lysine 27 trimethylation (H3K27me3), a repressive mark that plays a crucial role in the dynamic regulation of gene expression in plant development, to discuss recent advances as well as outstanding questions in the deposition, recognition, and removal of the mark and the impacts of these molecular processes on plant development.     

Glutathione as an Antioxidant and Regulatory Molecule in Plants Under Abiotic Stress Conditions

The glutathione (GSH)/glutathione disulfide (GSSG) redox couple is involved in several physiologic processes in plants under both optimal and stress conditions. It participates in the maintenance of redox homeostasis in the cells. The redox state of the GSH/GSSG couple is defined by its reducing capacity and the half-cell reduction potential, and differs in the various organs, tissues, cells, and compartments, changing during the growth and development of the plants. When characterizing this redox couple, the synthesis, degradation, oxidation, and transport of GSH and its conjugation with the sulfhydryl groups of other compounds should be considered. Under optimal growth conditions, the high GSH/GSSG ratio results in a reducing environment in the cells which maintains the appropriate structure and activity of protein molecules because of the inhibition of the formation of intermolecular disulfide bridges. In response to abiotic stresses, the GSH/GSSG ratio decreases due to the oxidation of GSH during the detoxification of reactive oxygen species (ROS) and changes in its metabolism. The lower GSH/GSSG ratio activates various defense mechanisms through a redox signalling pathway, which includes several oxidants, antioxidants, and stress hormones. In addition, GSH may control gene expression and the activity of proteins through glutathionylation and thiol-disulfide conversion. This review discusses the size and redox state of the GSH pool, including their regulation, their role in redox signalling and defense processes, and the changes caused by abiotic stress.     

Epigenetic transitions in germ cell development and meiosis

Germ cell development is controlled by unique gene expression programs and involves epigenetic reprogramming of histone modifications and DNA methylation. The central event is meiosis, during which homologous chromosomes pair and recombine, processes that involve histone alterations. At unpaired regions, chromatin is repressed by meiotic silencing. After meiosis, male germ cells undergo chromatin remodeling, including histone-to-protamine replacement. Male and female germ cells are also differentially marked by parental imprints, which contribute to sex determination in insects and mediate genomic imprinting in mammals. Here, we review epigenetic transitions during gametogenesis and discuss novel insights from animal and human studies.