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Project description:Exposure of plants to stress conditions or to certain chemical elicitors can establish a primed state, whereby responses to future stress encounters are enhanced. Stress priming can be long-lasting and likely involves epigenetic regulation of stress-responsive gene expression. However, the molecular events underlying priming are not well understood. Here, we characterise epigenetic changes in tomato plants primed for pathogen resistance by treatment with β-aminobutyric acid (BABA). We used whole genome bisulphite sequencing to construct tomato methylomes from control plants and plants treated with BABA at the seedling stage, and a parallel transcriptome analysis to identify genes primed for the response to inoculation by the fungal pathogen, Botrytis cinerea. Genomes of plants treated with BABA showed a significant reduction in global cytosine methylation, especially in CHH sequence contexts. Analysis of differentially methylated regions (DMRs) revealed that CHH DMRs were almost exclusively hypomethylated and were enriched in gene promoters and in DNA transposons located in the chromosome arms. Although there was some enrichment of stress response-related gene ontology terms in genes overlapping CHH DMRs, there was no significant enrichment of DMRs amongst a set of 747 primed defence genes, and nor was the pattern of methylation in these genes altered by BABA treatment. Hence, we conclude that whilst BABA treatment of tomato seedlings results in characteristic changes in genome-wide DNA methylation, CHH hypomethylation does not appear to directly target genes showing primed responses to pathogen infection. Instead, methylation may confer priming via in-trans regulation, acting at a distance from defence genes, and/or by targeting a smaller group of regulatory genes controlling stress responses.
2022-04-05 | GSE190780 | GEO
Project description:Long-lasting priming by β-amino butyric acid is marked by DNA hypomethylation
| PRJNA788469 | ENA
Project description:Long-lasting priming by β-amino butyric acid is marked by DNA hypomethylation.
| PRJNA788467 | ENA
Project description:Exposure of plants to stress conditions or to certain chemical elicitors can establish a primed state, whereby responses to future stress encounters are enhanced. Stress priming can be long-lasting and likely involves epigenetic regulation of stress-responsive gene expression. However, the molecular events underlying priming are not well understood. Here, we characterise epigenetic changes in tomato plants primed for pathogen resistance by treatment with β-aminobutyric acid (BABA). We used whole genome bisulphite sequencing to construct tomato methylomes from control plants and plants treated with BABA at the seedling stage, and a parallel transcriptome analysis to identify genes primed for the response to inoculation by the fungal pathogen, Botrytis cinerea. Genomes of plants treated with BABA showed a significant reduction in global cytosine methylation, especially in CHH sequence contexts. Analysis of differentially methylated regions (DMRs) revealed that CHH DMRs were almost exclusively hypomethylated and were enriched in gene promoters and in DNA transposons located in the chromosome arms. Genes overlapping CHH DMRs were enriched for a small number of stress response-related gene ontology terms. In addition, there was significant enrichment of DMRs in the promoters of genes that are differentially expressed in response to infection with B. cinerea. However, the majority of genes that demonstrated priming did not contain DMRs, and nor was the overall distribution of methylated cytosines in primed genes altered by BABA treatment. Hence, we conclude that whilst BABA treatment of tomato seedlings results in characteristic changes in genome-wide DNA methylation, CHH hypomethylation appears only to target a minority of genes showing primed responses to pathogen infection. Instead, methylation may confer priming via in-trans regulation, acting at a distance from defence genes, and/or by targeting a smaller group of regulatory genes controlling stress responses.
| S-EPMC9051511 | biostudies-literature
Project description:Compaction of T4 phage DNA (166 kbp) by short oligopeptide octamers composed of two types of amino acids, four cationic lysine (K), and four polar nonionic serine (S) having different sequence order was studied by single-molecule fluorescent microscopy. We found that efficient DNA compaction by oligopeptide octamers depends on the geometrical match between phosphate groups of DNA and cationic amines. The amino acid sequence order in octamers dramatically affects the mechanism of DNA compaction, which changes from a discrete all-or-nothing coil-globule transition induced by a less efficient (K4S4) octamer to a continuous compaction transition induced by a (KS)4 octamer with a stronger DNA-binding character. This difference in the DNA compaction mechanism dramatically changes the packaging density, and the morphology of T4 DNA condensates: DNA is folded into ordered toroidal or rod morphologies during all-or-nothing compaction, whereas disordered DNA condensates are formed as a result of the continuous DNA compaction. Furthermore, the difference in DNA compaction mechanism has a certain effect on the inhibition scenario of the DNA transcription activity, which is gradual for the continuous DNA compaction and abrupt for the all-or-nothing DNA collapse.
| S-EPMC6531782 | biostudies-literature
Project description:Constitutive expression of the immune checkpoint, PD-L1, inhibits anti-tumor immune responses in cancer, although the factors involved in PD-L1 regulation are poorly understood. Here we show that loss of global DNA methylation, particularly in intergenic regions and repeat elements, is associated with constitutive (PD-L1CON), versus inducible (PD-L1IND), PD-L1 expression in melanoma cell lines. We further show this is accompanied by transcriptomic up-regulation. De novo epigenetic regulators (e.g., DNMT3A) are strongly correlated with PD-L1 expression and methylome status. Accordingly, decitabine-mediated inhibition of global methylation in melanoma cells leads to increased PD-L1 expression. Moreover, viral mimicry and immune response genes are highly expressed in lymphocyte-negative plus PD-L1-positive melanomas, versus PD-L1-negative melanomas in The Cancer Genome Atlas (TCGA). In summary, using integrated genomic analysis we identified that global DNA methylation influences PD-L1 expression in melanoma, and hence melanoma's ability to evade anti-tumor immune responses. These results have implications for combining epigenetic therapy with immunotherapy.
| S-EPMC6147024 | biostudies-literature
Project description:Benzodiazepines are used for treating anxiety, epilepsy, muscle spasm, alcohol withdrawal, palliation, insomnia, and sedation as they allosterically modulate ?-amino-butyric acid type A (GABAA) receptors. Despite widespread use, the importance and mechanism of their immune side-effects are poorly understood. Herein we sought to elucidate the impact and mechanism of benzodiazepine-induced susceptibility to infection at anxiolytic doses in mice.Animal randomized controlled trial.Laboratory.Adult female C57BL/6 and BALB/c mice.The effect of a subsedative, anxiolytic dose of diazepam (2 mg kg intraperitoneal) was investigated in a murine Streptococcus pneumoniae pneumonia model.Mortality, bacterial and cytokine load, cell recruitment, and intracellular pH were measured. Diazepam treatment did not affect immune homeostasis in the lung. However, diazepam increased mortality and bacterial load from S. pneumoniae pneumonia. The increases in mortality and bacterial load were reversed by a GABAA antagonist, bicuculline, indicating dependence on GABAA receptor signaling. While cell recruitment was unaltered by diazepam, the cytokine response to infection was affected, suggesting that local responses to the pathogen were perturbed. Macrophage and monocytes expressed benzodiazepine sensitive (?1-?2) GABAA receptors. Interestingly macrophage GABAA receptor expression was regulated by bacterial toll-like receptor agonists and cytokines indicating an endogenous role in the immune response. Functionally diazepam appeared to counteract the endogenous down-regulation of GABAA signaling during infection. Consistent with augmented GABAA signaling, diazepam provoked intracellular acidosis in macrophage, leading to impaired cytokine production, bacterial phagocytosis and killing. In contrast, selective benzodiazepines that do not target the ?1 GABAA subunit did not affect macrophage function ex vivo or increase susceptibility to pneumonia in vivo.Our data highlight the regulation of macrophage function by GABAA receptor signaling and the potential harm of benzodiazepine exposure during pneumonia. Therapeutically, selective drugs may improve the safety profile of benzodiazepines.
| S-EPMC5774585 | biostudies-literature
Project description:Infants born to HIV-infected mothers are at high risk of becoming infected during gestation or the breastfeeding period. A search is thus warranted for vaccine formulations that will prevent mother-to-child HIV transmission. The LAMP/gag DNA chimeric vaccine encodes the HIV-1 p55gag fused to the lysosome-associated membrane protein-1 (LAMP-1) and has been shown to enhance anti-Gag antibody (Ab) and cellular immune responses in adult and neonatal mice; such a vaccine represents a new concept in antigen presentation. In this study, we evaluated the effect of LAMP/gag DNA immunization on neonates either before conception or during pregnancy. LAMP/gag immunization of BALB/c mice before conception by the intradermal route led to the transfer of anti-Gag IgG1 Ab through the placenta and via breastfeeding. Furthermore, there were an increased percentage of CD4+CD25+Foxp3+T cells in the spleens of neonates. When offspring were immunized with LAMP/gag DNA, the anti-Gag Ab response and the Gag-specific IFN-γ-secreting cells were decreased. Inhibition of anti-Gag Ab production and cellular responses were not observed six months after immunization, indicating that maternal immunization did not interfere with the long-lasting memory response in offspring. Injection of purified IgG in conjunction with LAMP/gag DNA immunization decreased humoral and cytotoxic T-cell responses. LAMP/gag DNA immunization by intradermal injection prior to conception promoted the transfer of Ab, leading to a diminished response to Gag without interfering with the development of anti-Gag T- and B-cell memory. Finally, we assessed responses after one intravenous injection of LAMP/gag DNA during the last five days of pregnancy. The intravenous injection led to in utero immunization. In conclusion, DNA vaccine enconding LAMP-1 with Gag and other HIV-1 antigens should be considered in the development of a protective vaccine for the maternal/fetal and newborn periods.
| S-EPMC3280311 | biostudies-literature
Project description:In the last decade, a paradigm shift has emerged in comparative immunology. Invertebrates can no longer be considered to be devoid of specific recognition and immune memory. However, we still lack a comprehensive view of these phenomena and their molecular mechanisms across phyla, especially in terms of duration, specificity, and efficiency in a natural context. In this study, we focused on a Lophotrochozoan/virus interaction, as antiviral priming is mostly overlooked in molluscs. Juvenile Crassostrea gigas oysters experience reoccurring mass mortalities events from Ostreid herpes virus 1 with no existing therapeutic treatment. Our results showed that various nucleic acid injections can prime oysters to trigger an antiviral state ultimately protecting them against a subsequent viral infection. Focusing on poly(I:C) as elicitor, we evidenced that it protected from an environmental infection, by mitigating viral replication. That protection seemed to induce a specific antiviral response as poly(I:C) fails to protect against a pathogenic bacteria. Finally, we showed that this phenomenon was long-lasting, persisting for at least 5 months thus suggesting for the first time the existence of innate immune memory in this invertebrate species. This study strengthens the emerging hypotheses about the broad conservation of innate immune priming and memory mechanisms in Lophotrochozoans.
| S-EPMC5640609 | biostudies-literature
Project description:Anxiety and stress disorders are a major public health issue. However, their pathophysiology is still unclear. The gamma amino acid butyric acid (GABA) neurochemical system has been strongly implicated in their pathogenesis and treatment by numerous preclinical and clinical studies, the most recent of which have been highlighted and critical review in this paper. Changes in cortical GABA appear related to normal personality styles and responses to stress. While there is accumulating animal and human neuroimaging evidence of cortical and subcortical GABA deficits across a number of anxiety conditions, a clear pattern of findings in specific brain regions for a given disorder is yet to emerge. Neuropsychiatric conditions with anxiety as a clinical feature may have GABA deficits as an underlying feature. Different classes of anxiolytic therapies support GABA function, and this may be an area in which newer GABA neuroimaging techniques could soon offer more personalized therapy. Novel GABAergic pharmacotherapies in development offer potential improvements over current therapies in reducing sedative and physiologic dependency effects, while offering rapid anxiolysis.
| S-EPMC4804267 | biostudies-literature