Epi-Drugs in Heart Failure

Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure

Intragenic DNA methylation prevents spurious transcription initiation.

In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cance

Gene environment-interaction and cardiovascular phenotype in obesity and diabetes

Although a large body of evidence supports the notion that genes determine cardio-metabolic traits and outcomes, the non-genetic regulation of these events has recently gained increasing attention. Plastic chemical modifications of DNA-histone complexes defined epigenetic changes regulate gene expression by modifying chromatin accessibility to transcription factors. In the present thesis, we have investigated the emerging role of epigenetic modifications as fine-tuning regulators of gene expression in diabetic cardiomyopathy, as well as in obesity and diabetes-driven endothelial dysfunction. Study I: The objective was to investigate whether mitochondrial adaptor p66Shc contributes to obesity-related vascular dysfunction. Oxidative stress and vascular expression of chromatin modifying enzymes were investigated in visceral fat arteries (VFA) from obese and age- matched healthy subjects. VFA from obese patients displayed enhanced mitochondrial reactive oxygen species (ROS) and endothelial dysfunction as well as a significant dysregulation of chromatin modifier enzymes methyltransferase SUV39H1, demethylase JMJD2C and acetyltransferase SRC-1 as compared to control VFA. These changes were associated with reduced methylation and acetylation of histone 3 lysine 9 (H3K9) on p66Shc promoter. Specifically, we demonstrated that obesity-induced downregulation of SUV39H1 orchestrates JMJD2C/SRC-1 recruitment to p66Shc promoter, fostering adverse H3K9 remodeling and p66Shc upregulation. Study II: We sought to investigate whether epigenetic regulation of pro-oxidant adaptor p66Shc contributes to persistent myocardial dysfunction despite intensive glycemic control (IGC). p66Shc expression was increased in the heart of diabetic mice, and IGC did not revert this phenomenon. Dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 linked to upregulation of miRNAs (miR-218 and miR-34a) drive persistent transcription of the adaptor p66Shc, thereby leading to mitochondrial oxidative stress, myocardial inflammation and left ventricular dysfunction. Our findings showed that adverse epigenetic signatures on p66Shc promoter contribute to left ventricular (LV) dysfunction in the setting of diabetes. Study III: Here we demonstrate for the first time a protective role of activated protein-1 (AP-1) transcription factor JunD against derangement of ROS homeostasis, inflammation and myocardial impairment in the setting of diabetes-induced hyperglycemia. JunD transcriptional activity was reduced in the heart of wild-type mice with streptozotocin- induced diabetes and was associated with downregulation of free radical scavengers, increased expression of ROS-generating NADPH oxidase and marked increase in myocardial superoxide anion generation. These redox changes were paralleled by activation of NF-κB- dependent inflammatory pathways and left ventricular dysfunction. Interestingly enough, such detrimental changes did not occur in diabetic mice with cardiac-specific overexpression of JunD (α-MHC-JunDtg) and LV function was not impaired, indicating the relevant role of JunD in counteracting hyperglycemia-induced redox changes and cardiac damage in diabetes. Study IV: Enhancer of zeste homologue 2 (EZH2), a member of the family of SET1 methyltransferase and a catalytic component in the polycomb repressive complex 2, is associated with transcriptional repression through histone H3K27me3 modification. Therefore, we hypothesize that its pharmacological modulation could have an impact on hyperglycemia-driven endothelial dysfunction. We demonstrated that pharmacological inhibition of EZH2 by GSK126 might prevent key hallmarks of diabetic vascular dysfunction, such as oxidative stress and inflammation. Experiments in human aortic endothelial cells showed that GSK126 protects against hyperglycemia-induced oxidative stress and inflammation via restoration of JunD, SOD1 and SOD2 expression and inhibition of Nox4 upregulation. Moreover, GSK126 was able to prevent activation of transcription factor NF-kB and subsequent upregulation of inflammatory adhesion molecules IL-6 and MCP-1. Altogether, our studies provide novel molecular insights on the regulation of redox and inflammatory pathways implicated in the impairment of obesity and diabetes-induced endothelial and cardiac function. Moreover, by targeting epigenetic changes responsible of derailed pro-oxidant and pro-inflammatory transcriptional programmes, we shed some light on putative pharmacological strategies to reduce the burden of cardiovascular disease in this setting

Drought stress tolerance in rice: a critical insight

Drought is currently a serious threat for farming especially in rice cultivation, due to its substantial water requirements throughout its lifecycle. Drought is one of the major environmental constraints disrupting the growth and yield of rice plants, affecting them at physiological, morphological, biochemical and molecular levels. Global climate change exacerbates this issue, leading to substantial economic losses. As rice is a major food crop worldwide, the demand for rice production is increasing in tandem with the expanding human population. Consequently, it has become imperative to utilize drought-prone areas for agriculture and develop drought-tolerant rice genotypes. In addition to conventional breeding methods, the application of multi-omics approaches proves most effective in meeting the need to enhance drought tolerance in rice plants. Protective mechanisms, such as morphological adaptation, physiological acclimatization, cellular adjustments and antioxidant defense, play pivotal roles in helping plants overcome drought stress. Plant-microbial interactions are important for plants to overcome drought-induced adversities. Furthermore, applications of conventional approaches, omics approaches and nanotechnology are very promising for generating climate smart agriculture. Our aim in this review is to focus on drought stress tolerance in rice including drought-tolerant rice genotypes, their adaptation mechanisms, the unveiling the genes, transcription factors, microRNAs (miRNA) involved, microbial assistance and exploring approaches to mitigate drought stress in rice plants. The present review might throw some light on understanding the mechanism of drought stress tolerance in rice, including its molecular crosstalk and biochemical dynamics, for future researchers