Potential Role Of Epigenetic Mechanisms Research Articles

Liver epigenomic signature associated with chronic oxidative stress in a mouse model of glutathione deficiency

Oxidative stress is intimately involved in the pathogenesis of fatty liver disease (FLD). A major factor contributing to oxidative stress is the depletion of the ubiquitous antioxidant glutathione (GSH). Unexpectedly, chronic GSH deficiency renders glutamate-cysteine ligase modifier subunit (Gclm)-null mice protected from fatty liver injuries. Epigenetic regulation serves as an important cellular mechanism in modulating gene expression and disease outcome in FLD, although it is not well understood how systemic redox imbalance modifies the liver epigenome. In the current study, utilizing the Gclm-null mouse model, we aimed to elucidate redox-associated epigenomic changes and their implications in liver stress response. We performed high-throughput array-based DNA methylation profiling (MeDIP array) in 22,327 gene promoter regions (from −1300 bp to +500 bp of the Transcription Start Sites) in the liver and peripheral blood cells. Results from the MeDIP array demonstrate that, although global methylation enrichment in gene promoters did not change, low GSH resulted in prevalent demethylation at the individual promoter level. Such an effect likely attributed to a declined availability of the methyl donor S-adenosyl methionine (SAM) in Gclm-null liver. Functional enrichment analysis of liver target genes is suggestive of a potential role of epigenetic mechanisms in promoting cellular survival and lipid homeostasis in Gclm-null liver. In comparison with the liver tissue, MeDIP array in peripheral blood cells revealed a panel of 19 gene promoters that are candidate circulating biomarkers for hepatic epigenomic changes associated with chronic GSH deficiency. Collectively, our results provided new insights into the in vivo interplay between liver redox state and DNA methylation status. The current study laid the groundwork for future epigenetic/epigenomic investigations in experimental settings or human populations under conditions of liver oxidative stress induced by environmental or dietary challenges.

Evidence of epigenetic landscape shifts in mucopolysaccharidosis IIIB and IVA

Lysosomal storage diseases (LSDs) are a group of monogenic diseases characterized by mutations in genes coding for proteins associated with the lysosomal function. Despite the monogenic nature, LSDs patients exhibit variable and heterogeneous clinical manifestations, prompting investigations into epigenetic factors underlying this phenotypic diversity. In this study, we focused on the potential role of epigenetic mechanisms in the pathogenesis of mucopolysaccharidosis IIIB (MPS IIIB) and mucopolysaccharidosis IVA (MPS IVA). We analyzed DNA methylation (5mC) and histone modifications (H3K14 acetylation and H3K9 trimethylation) in MPS IIIB and MPS IVA patients’ fibroblasts and healthy controls. The findings revealed that global DNA hypomethylation is present in cell lines for both diseases. At the same time, histone acetylation was increased in MPS IIIB and MPS IVA cells in a donor-dependent way, further indicating a shift towards relaxed open chromatin in these MPS. Finally, the constitutive heterochromatin marker, histone H3K9 trimethylation, only showed reduced clustering in MPS IIIB cells, suggesting limited alterations in heterochromatin organization. These findings collectively emphasize the significance of epigenetic mechanisms in modulating the phenotypic variations observed in LSDs. While global DNA hypomethylation could contribute to the MPS pathogenesis, the study also highlights individual-specific epigenetic responses that might contribute to phenotypic heterogeneity. Further research into the specific genes and pathways affected by these epigenetic changes could provide insights into potential therapeutic interventions for these MPS and other LSDs.

The Potential Role of Epigenetic Mechanisms in the Development of Retinitis Pigmentosa and Related Photoreceptor Dystrophies.

Retinitis pigmentosa and related photoreceptor dystrophies (RPRPD) are rare retinal diseases caused by hereditary gene mutations resulting in photoreceptor death, followed by vision loss. While numerous genes involved in these diseases have been identified, many cases have still not been associated with any gene, indicating that new mechanisms may be involved in the pathogenesis of these photoreceptor dystrophies. Many genes associated with RPRPD regulate photoreceptor specification and maturation in the developing retina. Since retinal development begins with a population of equivalent, proliferating retinal progenitor cells (RPCs) having a specific “competence” in generating all types of retinal neurons, including cone and rod photoreceptors, we tested the epigenetic changes in promoters of genes required for photoreceptor development and genes associated with RPRPD during RPC differentiation into cone and rod photoreceptors. We found that promoters of many of these genes are epigenetically repressed in RPCs but have no epigenetic restrictions in photoreceptors. Our findings also suggest that DNA methylation as an epigenetic mark, and DNA demethylation as a process, are more important than other epigenetic marks or mechanisms in the pathogenesis of these diseases. Most notably, irregularities in the DNA demethylation process during the RPC-to-photoreceptor transition may significantly contribute to retinitis pigmentosa (RP) pathogenesis since genes with hypermethylated promoters in RPCs account for at least 40% of autosomal recessive RP cases and at least 30% of autosomal dominant RP cases. Thus, we proposed an epigenetic model according to which unsuccessful demethylation of regulatory sequences (e.g., promoters, enhancers) of genes required for photoreceptor development, maturation, and function during the RPC-to-photoreceptor transition may reduce or even eliminate their activity, leading to RPRPD without any inheritable mutations in these genes.

Intersection of Epigenetic and Immune Alterations: Implications for Fetal Alcohol Spectrum Disorder and Mental Health.

Prenatal alcohol exposure can impact virtually all body systems, resulting in a host of structural, neurocognitive, and behavioral abnormalities. Among the adverse impacts associated with prenatal alcohol exposure are alterations in immune function, including an increased incidence of infections and alterations in immune/neuroimmune parameters that last throughout the life-course. Epigenetic patterns are also highly sensitive to prenatal alcohol exposure, with widespread alcohol-related alterations to epigenetic profiles, including changes in DNA methylation, histone modifications, and miRNA expression. Importantly, epigenetic programs are crucial for immune system development, impacting key processes such as immune cell fate, differentiation, and activation. In addition to their role in development, epigenetic mechanisms are emerging as attractive candidates for the biological embedding of environmental factors on immune function and as mediators between early-life exposures and long-term health. Here, following an overview of the impact of prenatal alcohol exposure on immune function and epigenetic patterns, we discuss the potential role for epigenetic mechanisms in reprogramming of immune function and the consequences for health and development. We highlight a range of both clinical and animal studies to provide insights into the array of immune genes impacted by alcohol-related epigenetic reprogramming. Finally, we discuss potential consequences of alcohol-related reprogramming of immune/neuroimmune functions and their effects on the increased susceptibility to mental health disorders. Overall, the collective findings from animal models and clinical studies highlight a compelling relationship between the immune system and epigenetic pathways. These findings have important implications for our understanding of the biological mechanisms underlying the long-term and multisystem effects of prenatal alcohol exposure, laying the groundwork for possible novel interventions and therapeutic strategies to treat individuals prenatally exposed to alcohol.

Gene expression and epigenetic responses of the marine Cladoceran, Evadne nordmanni, and the copepod, Acartia clausi, to elevated CO2.

Characterizing the capacity of marine organisms to adapt to climate change related drivers (e.g., pCO2 and temperature), and the possible rate of this adaptation, is required to assess their resilience (or lack thereof) to these drivers. Several studies have hypothesized that epigenetic markers such as DNA methylation, histone modifications and noncoding RNAs, act as drivers of adaptation in marine organisms, especially corals. However, this hypothesis has not been tested in zooplankton, a keystone organism in marine food webs. The objective of this study is to test the hypothesis that acute ocean acidification (OA) exposure alters DNA methylation in two zooplanktonic species—copepods (Acartia clausii) and cladocerans (Evadne nordmanii). We exposed these two species to near‐future OA conditions (400 and 900 ppm pCO2) for 24 h and assessed transcriptional and DNA methylation patterns using RNA sequencing and Reduced Representation Bisulfite Sequencing (RRBS). OA exposure caused differential expression of genes associated with energy metabolism, cytoskeletal and extracellular matrix functions, hypoxia and one‐carbon metabolism. Similarly, OA exposure also caused altered DNA methylation patterns in both species but the effect of these changes on gene expression and physiological effects remains to be determined. The results from this study form the basis for studies investigating the potential role of epigenetic mechanisms in OA induced phenotypic plasticity and/or adaptive responses in zooplanktonic organisms.

The Emerging Role of Epigenetics in Therapeutic Targeting of Cardiomyopathies.

Cardiomyopathies (CMPs) are a heterogeneous group of myocardial diseases accountable for the majority of cases of heart failure (HF) and/or sudden cardiac death (SCD) worldwide. With the recent advances in genomics, the original classification of CMPs on the basis of morphological and functional criteria (dilated (DCM), hypertrophic (HCM), restrictive (RCM), and arrhythmogenic ventricular cardiomyopathy (AVC)) was further refined into genetic (inherited or familial) and acquired (non-inherited or secondary) forms. Despite substantial progress in the identification of novel CMP-associated genetic variations, as well as improved clinical recognition diagnoses, the functional consequences of these mutations and the exact details of the signaling pathways leading to hypertrophy, dilation, and/or contractile impairment remain elusive. To date, global research has mainly focused on the genetic factors underlying CMP pathogenesis. However, growing evidence shows that alterations in molecular mediators associated with the diagnosis of CMPs are not always correlated with genetic mutations, suggesting that additional mechanisms, such as epigenetics, may play a role in the onset or progression of CMPs. This review summarizes published findings of inherited CMPs with a specific focus on the potential role of epigenetic mechanisms in regulating these cardiac disorders.

The first mitochondrial 5-methylcytosine map in a non-model teleost (Oreochromis niloticus) reveals extensive strand-specific and non-CpG methylation

DNA methylation is one of the main epigenetic mechanisms that regulate gene expression in a manner that depends on the genomic context and varies considerably across taxa. This DNA modification was first found in nuclear genomes of eukaryote several decades ago and it has also been described in mitochondrial DNA. It has recently been shown that mitochondrial DNA is extensively methylated in mammals and other vertebrates. Our current knowledge of mitochondrial DNA methylation in fish is very limited, especially in non-model teleosts. In this study, using whole-genome bisulfite sequencing, we determined methylation patterns within non-CpG (CH) and CpG (CG) contexts in the mitochondrial genome of Nile tilapia, a non-model teleost of high economic importance. Our results demonstrate the presence of mitochondrial DNA methylation in this species predominantly within a non-CpG context, similarly to mammals. We found a strand-specific distribution of methylation, in which highly methylated cytosines were located on the minus strand. The D-loop region had the highest mean methylation level among all mitochondrial loci. Our data provide new insights into the potential role of epigenetic mechanisms in regulating metabolic flexibility of mitochondria in fish, with implications in various biological processes, such as growth and development.

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

BackgroundThe discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.ResultsWe conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.ConclusionOur study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.

The association between maternal folic acid supplementation and risk of childhood leukeamia: a systematic review focusing on the potential role of epigenetic mechanisms

Rationale: Folate is considered a key nutrient especially during embryogenesis. Consumption of folate doses during periconceptional period and pregnancy, has been linked to modifications of the epigenetic mechanisms and gene expression in the fetus. It has been hypothesized that insufficient intake of maternal folate could result in impairment of methylgroup supply, altered DNA methylation and carcinogenesis both in utero and in early life. This systematic review aimed to explore the effect of maternal folic acid supplementation on the development of childhood leukaemia, the most common type of peadiatric cancer.

The Impact of Milk and Its Components on Epigenetic Programming of Immune Function in Early Life and Beyond: Implications for Allergy and Asthma.

Specific and adequate nutrition during pregnancy and early life is an important factor in avoiding non-communicable diseases such as obesity, type 2 diabetes, cardiovascular disease, cancers, and chronic allergic diseases. Although epidemiologic and experimental studies have shown that nutrition is important at all stages of life, it is especially important in prenatal and the first few years of life. During the last decade, there has been a growing interest in the potential role of epigenetic mechanisms in the increasing health problems associated with allergic disease. Epigenetics involves several mechanisms including DNA methylation, histone modifications, and microRNAs which can modify the expression of genes. In this study, we focus on the effects of maternal nutrition during pregnancy, the effects of the bioactive components in human and bovine milk, and the environmental factors that can affect early life (i.e., farming, milk processing, and bacterial exposure), and which contribute to the epigenetic mechanisms underlying the persistent programming of immune functions and allergic diseases. This knowledge will help to improve approaches to nutrition in early life and help prevent allergies in the future.

Drug Resistance in Cancer Therapy and the Role of Epigenetics.

Effective leukemia treatment is seriously hampered by drug resistance, and the potential role of epigenetic mechanisms in cancer drug resistance has recently been investigated. With conventional anticancer drugs, including alkylating drugs, anti-metabolite drugs, topoisomerase inhibitors, and microtubule inhibitors-which have been available for half a century-drug resistance often develops because of decreased expression of target enzymes, in conjunction with increased expression of drug export pumps. Alterations of target gene expression and increased export pump function might be caused by epigenetic changes, such as alterations in methylation status, as well as by changes in histone acetylation status. In addition, newly developed anticancer drugs, including small-molecule drugs, such as kinase inhibitors, antibody drugs, and immune modulatory drugs, also resulted in development of drug resistance within 1 year, although these drugs showed significant effectiveness for patients resistant to conventional anticancer drugs. The resistant cells exhibited increased expression of bypass pathways, activation of downstream cascades, decreased expression of antigens of tumor cells, increased DNA repair activity, and increased expression of drug export pumps, which also suggests the presence of epigenetic changes. This article reviews drug resistance in cancer therapy and the possible roles of epigenetic mechanisms.

TCDD Toxicity Mediated by Epigenetic Mechanisms.

Dioxins are highly toxic and persistent halogenated organic pollutants belonging to two families i.e., Polychlorinated Dibenzo-p-Dioxins (PCDDs) and Polychlorinated Dibenzo Furans (PCDFs). They can cause cancer, reproductive and developmental issues, damage to the immune system, and can deeply interfere with the endocrine system. Dioxins toxicity is mediated by the Aryl-hydrocarbon Receptor (AhR) which mediates the cellular metabolic adaptation to these planar aromatic xenobiotics through the classical transcriptional regulation pathway, including AhR binding of ligand in the cytosol, translocation of the receptor to the nucleus, dimerization with the AhR nuclear translocator, and the binding of this heterodimeric transcription factor to dioxin-responsive elements which regulate the expression of genes involved in xenobiotic metabolism. 2,3,7,8-TCDD is the most toxic among dioxins showing the highest affinity toward the AhR receptor. Beside this classical and well-studied pathway, a number of papers are dealing with the role of epigenetic mechanisms in the response to environmental xenobiotics. In this review, we report on the potential role of epigenetic mechanisms in dioxins-induced cellular response by inspecting recent literature and focusing our attention on epigenetic mechanisms induced by the most toxic 2,3,7,8-TCDD.

Potential role for histone deacetylation in chronic diazepam-induced downregulation of α1-GABAA receptor subunit expression.

Corroborating evidence indicate that the downregulation of GABAA receptor subunit expression may underlie tolerance to the anticonvulsant and anxiolytic actions of benzodiazepine (BZ) ligands that act as full allosteric modulators (FAMs) of GABA actions at a variety of GABAA receptor subtypes. We and others have shown that 10‐14 days treatment with increasing doses of diazepam (a FAM) resulted in anticonvulsant tolerance and decreased the expression of the α1 GABAA receptor subunit mRNA and protein in frontal cortex. In addition, we have also shown that long‐term treatment with imidazenil, a partial allosteric modulator of GABA action at selective GABAA receptor subtypes, fail to change the expression of the α1 subunit mRNA or induce tolerance to its anticonvulsant or anxiolytic action. However, little is known regarding the potential role of epigenetic mechanisms on long‐term BZ‐induced downregulation of GABAA receptor subunit. Therefore, we examined the role of histone acetylation and DNA methylation mechanisms on long‐term diazepam‐induced downregulation of the α1 subunit mRNA expression in rat frontal cortex. We found that 10 days treatment with increasing doses of diazepam but not imidazenil decreased the expression of the α1 GABAA receptor subunit mRNA and promoter acetylation in frontal cortex. In addition, we also found that 10 days treatment with diazepam but not imidazenil increased the expression of histone deacetylase (HDAC) 1 and 2 in frontal cortex. Thus, the increased expression of HDAC1 and HDAC2 (class 1 HDACs) and consequently increased histone deacetylation mechanism of this class 1 HDACs, may underlie long‐term diazepam‐induced decreased expression of the α1 GABAA receptor subunit mRNA in frontal cortex.

Synthesizing the role of epigenetics in the response and adaptation of species to climate change in freshwater ecosystems.

Freshwater ecosystems are amongst the most threatened ecosystems on Earth. Currently, climate change is one of the most important drivers of freshwater transformation and its effects include changes in the composition, biodiversity and functioning of freshwater ecosystems. Understanding the capacity of freshwater species to tolerate the environmental fluctuations induced by climate change is critical to the development of effective conservation strategies. In the last few years, epigenetic mechanisms were increasingly put forward in this context because of their pivotal role in gene-environment interactions. In addition, the evolutionary role of epigenetically inherited phenotypes is a relatively recent but promising field. Here, we examine and synthesize the impacts of climate change on freshwater ecosystems, exploring the potential role of epigenetic mechanisms in both short- and long-term adaptation of species. Following this wrapping-up of current evidence, we particularly focused on bringing together the most promising future research avenues towards a better understanding of the effects of climate change on freshwater biodiversity, specifically highlighting potential molecular targets and the most suitable freshwater species for future epigenetic studies in this context.

Epigenetic regulation of EC-SOD expression in aging lung fibroblasts: Role of histone acetylation

Lung disorders characterized by fibroproliferation and excessive deposition of extracellular matrices occur in late adulthood, and their pathological manifestations become more prominent with aging. The exact mechanisms linking aging and fibroproliferative disorders are unknown, but increased oxidative stress resulting in the accumulation of damaged proteins, DNA, and lipids is considered a major factor. In the lung, and especially in the pulmonary fibroblasts, the extracellular superoxide dismutase (EC-SOD) is a major antioxidant enzyme that has been implicated in pulmonary fibrosing disorders, among others. Here, we investigate the regulation of EC-SOD in pulmonary lung fibroblasts derived from young (up to 3 month) and old (24 month) C57BL6 mice. We found that old fibroblasts have marginally elevated levels of reactive oxidant species (ROS), which coincides with attenuated expression a number of antioxidant enzymes including EC-SOD. Exposure of old fibroblasts to the DNA methyltransferase inhibitor 5-aza-dC did not restore expression of EC-SOD. On the other hand, repression of EC-SOD expression was associated with deacetylation of lysine 9 on histone H3 and lysines 5, 8, 12 and 16 on histone H4 located at the gene promoter. Interestingly, the repressive tri-methylation of lysine 27 on histone H3 was elevated in old compared to young fibroblasts. In addition, exposure of old lung fibroblasts to HDAC class 1 and class 2 inhibitors restored EC-SOD expression to the level observed in young fibroblasts. While the exact mechanism of age-dependent downregulation of EC-SOD is yet to be defined, our studies indicate a potential role of epigenetic mechanisms including histone deacetylation in this process.

Genetic and epigenetic variation in Spartina alterniflora following the Deepwater Horizon oil spill.

Catastrophic events offer unique opportunities to study rapid population response to stress in natural settings. In concert with genetic variation, epigenetic mechanisms may allow populations to persist through severe environmental challenges. In 2010, the Deepwater Horizon oil spill devastated large portions of the coastline along the Gulf of Mexico. However, the foundational salt marsh grass, Spartina alterniflora, showed high resilience to this strong environmental disturbance. Following the spill, we simultaneously examined the genetic and epigenetic structure of recovering populations of S. alterniflora to oil exposure. We quantified genetic and DNA methylation variation using amplified fragment length polymorphism and methylation sensitive fragment length polymorphism (MS‐AFLP) to test the hypothesis that response to oil exposure in S. alterniflora resulted in genetically and epigenetically based population differentiation. We found high genetic and epigenetic variation within and among sites and found significant genetic differentiation between contaminated and uncontaminated sites, which may reflect nonrandom mortality in response to oil exposure. Additionally, despite a lack of genomewide patterns in DNA methylation between contaminated and uncontaminated sites, we found five MS‐AFLP loci (12% of polymorphic MS‐AFLP loci) that were correlated with oil exposure. Overall, our findings support genetically based differentiation correlated with exposure to the oil spill in this system, but also suggest a potential role for epigenetic mechanisms in population differentiation.

The Histone Modification Code in the Pathogenesis of Autoimmune Diseases.

Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases. Histone modifications regulate the chromatin states and gene transcription without any change in the DNA sequence, possibly resulting in phenotype alteration in several different cell types. In this paper, we discuss the significant roles of histone modifications involved in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and type 1 diabetes.

Epigenetic Mechanisms in Asthma.

Asthma and allergic diseases are among the most prevalent chronic noncommunicable diseases of childhood, but the underlying pathogenetic mechanisms are poorly understood. Because epigenetic mechanisms link gene regulation to environmental cues and developmental trajectories, their contribution to asthma and allergy pathogenesis is under active investigation. DNA methylation signatures associated with concurrent disease and with the development of asthma during childhood asthma have been identified, but their significance is not easily interpretable. On the other hand, the characterization of early epigenetic predictors of asthma points to a potential role of epigenetic mechanisms in regulating the inception of, and the susceptibility to, this disease.

The Mechanisms Underlying Chronic Inflammation in Rheumatoid Arthritis from the Perspective of the Epigenetic Landscape.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that is characterized by synovial hyperplasia and progressive joint destruction. The activation of RA synovial fibroblasts (SFs), also called fibroblast-like synoviocytes (FLS), contributes significantly to perpetuation of the disease. Genetic and environmental factors have been reported to be involved in the etiology of RA but are insufficient to explain it. In recent years, accumulating results have shown the potential role of epigenetic mechanisms, including histone modifications, DNA methylation, and microRNAs, in the development of RA. Epigenetic mechanisms regulate chromatin state and gene transcription without any change in DNA sequence, resulting in the alteration of phenotypes in several cell types, especially RASFs. Epigenetic changes possibly provide RASFs with an activated phenotype. In this paper, we review the roles of epigenetic mechanisms relevant for the progression of RA.

Methylome analysis reveals an important role for epigenetic changes in the regulation of the Arabidopsis response to phosphate starvation

Phosphate (Pi) availability is a significant limiting factor for plant growth and productivity in both natural and agricultural systems. To cope with such limiting conditions, plants have evolved a myriad of developmental and biochemical strategies to enhance the efficiency of Pi acquisition and assimilation to avoid nutrient starvation. In the past decade, these responses have been studied in detail at the level of gene expression; however, the possible epigenetic components modulating plant Pi starvation responses have not been thoroughly investigated. Here, we report that an extensive remodeling of global DNA methylation occurs in Arabidopsis plants exposed to low Pi availability, and in many instances, this effect is related to changes in gene expression. Modifications in methylation patterns within genic regions were often associated with transcriptional activation or repression, revealing the important role of dynamic methylation changes in modulating the expression of genes in response to Pi starvation. Moreover, Arabidopsis mutants affected in DNA methylation showed that changes in DNA methylation patterns are required for the accurate regulation of a number of Pi-starvation-responsive genes and that DNA methylation is necessary to establish proper morphological and physiological phosphate starvation responses.