Alterations In DNA Sequence Research Articles

The co-occurrence of genetic variants in the TYR and OCA2 genes confers susceptibility to albinism

Although rare genetic conditions are mostly caused by DNA sequence alterations that functionally disrupt individual genes, large-scale studies using genome sequencing have started to unmask additional complexity. Understanding how combinations of variants in different genes shape human phenotypes is expected to provide important insights into the clinical and genetic heterogeneity of rare disorders. Here, we use albinism, an archetypal rare condition associated with hypopigmentation, as an exemplar for the study of genetic interactions. We analyse data from the Genomics England 100,000 Genomes Project alongside a cohort of 1120 individuals with albinism, and investigate the effect of dual heterozygosity for the combination of two established albinism-related variants: TYR:c.1205 G > A (p.Arg402Gln) [rs1126809] and OCA2:c.1327 G > A (p.Val443Ile) [rs74653330]. As each of these changes alone is insufficient to cause disease when present in the heterozygous state, we sought evidence of synergistic effects. We show that, when both variants are present, the probability of receiving a diagnosis of albinism is significantly increased (odds ratio 12.8; 95% confidence interval 6.0 – 24.7; p-value 2.1 ×10−8). Further analyses in an independent cohort, the UK Biobank, support this finding and highlight that heterozygosity for the TYR:c.1205 G > A and OCA2:c.1327 G > A variant combination is associated with statistically significant alterations in visual acuity and central retinal thickness (traits that are considered albinism endophenotypes). The approach discussed in this report opens up new avenues for the investigation of oligogenic patterns in apparently Mendelian disorders.

Deciphering Depression: Epigenetic Mechanisms and Treatment Strategies.

Depression, a significant mental health disorder, is under intense research scrutiny to uncover its molecular foundations. Epigenetics, which focuses on controlling gene expression without altering DNA sequences, offers promising avenues for innovative treatment. This review explores the pivotal role of epigenetics in depression, emphasizing two key aspects: (I) identifying epigenetic targets for new antidepressants and (II) using personalized medicine based on distinct epigenetic profiles, highlighting potential epigenetic focal points such as DNA methylation, histone structure alterations, and non-coding RNA molecules such as miRNAs. Variations in DNA methylation in individuals with depression provide opportunities to target genes that are associated with neuroplasticity and synaptic activity. Aberrant histone acetylation may indicate that antidepressant strategies involve enzyme modifications. Modulating miRNA levels can reshape depression-linked gene expression. The second section discusses personalized medicine based on epigenetic profiles. Analyzing these patterns could identify biomarkers associated with treatment response and susceptibility to depression, facilitating tailored treatments and proactive mental health care. Addressing ethical concerns regarding epigenetic information, such as privacy and stigmatization, is crucial in understanding the biological basis of depression. Therefore, researchers must consider these issues when examining the role of epigenetics in mental health disorders. The importance of epigenetics in depression is a critical aspect of modern medical research. These findings hold great potential for novel antidepressant medications and personalized treatments, which would significantly improve patient outcomes, and transform psychiatry. As research progresses, it is expected to uncover more complex aspects of epigenetic processes associated with depression, enhance our comprehension, and increase the effectiveness of therapies.

P-804 Smchd1 is a key regulator of epigenetic cellular memory induced by morphine in mouse embryonic stem cells (mESC)

Abstract Study question Can morphine induce stable epigenetic changes that persist mitotically in mESC? Summary answer SMCHD1 is a key regulator of epigenetic cellular memory induced by morphine, whose deregulation can be memorized by mESC and upon embryo development. What is known already Epigenetic cellular memory induced by environmental factors implies the existence of mitotically heritable changes that influence gene expression without altering DNA sequence, leading to the propagation of heritable changes in phenotype. X chromosome inactivation (XCI) is an important epigenetic process, which takes places during embryo development and is maintained in the adulthood. Since XCI is part of normal development, changes induced by environmental factors might affect embryo development and lead to health problems. As morphine can easily pass through the placental barrier and reach the embryo, our aim is to elucidate whether morphine causes epigenetic regulation on XCI process. Study design, size, duration Epigenetic cellular memory induced by environmental factors implies the existence of mitotically heritable changes that influence gene expression without altering DNA sequence, leading to the propagation of heritable changes in phenotype. To evaluate if morphine can induce cellular epigenetic memory, we analyzed the dynamic epigenetic changes over the time in the absence of morphine. For that purpose, OCT4-reported mESCs were chronically treated with morphine during 24h (10-5 mM) Participants/materials, setting, methods • Transcriptomic analysis by RNA-Sequencing and gene expression validation by qRT-PCR. • Epigenetic analysis by H3K27me3 ChIP-Sequencing and WGBS-Sequencing. • Smchd1 gene silencing by Crisper-Cas9. Main results and the role of chance Morphine induced cellular epigenetic memory upon embryo development. mESCs can memorize morphine exposure and induces transcriptional changes that can persist over the time, even in the absence of morphine. RNA-seq has shown that morphine chronic treatment produces a transcriptional deregulation of 932 genes in P1 just after the treatment and this amount increased after treatment withdrawal (1196 genes, P2 and 2138 in P3). Integrative analyses between P1, P2 and P3 identifies Smchd1 gene as a potential regulator of epigenetic cellular memory induced by morphine. Crisper-Cas9 silencing analyses confirmed that Structural maintenance of chromosomes flexible hinge domain-containing 1 (Smchd1), an architectural factor critical for X-chromosome inactivation (XCI), is a morphine-sensitive target gene. Morphine reduced the gene expression of Smchd1 in mESC at different time points, which is consistent with an increase of H3K27me3 and DNA methylation at promoter. Morphine alters normal X chromosome wide silencing. Our results identified Smchd1 a key regulator of epigenetic cellular memory induced by morphine, whose deregulation can be memorized by the cell, providing an epigenetic mechanism that is maintained into cell-to-cell memory and cell differentiation process, which might cause diseases or health problems during the adulthood. Limitations, reasons for caution To perform the in-vitro analysis in mouse Wider implications of the findings Our results provide insights into the epigenetic mechanisms induced by morphine and establish the bases to understand how environmental factors can cause epigenetic changes that cause health problems or diseases, since a skewed XCI pattern is behind the higher incidence on different neurological diseases such as Alzheimer or Autism Trial registration number not applicable

Microbial Synthetic Epigenetic Tools Design and Applications.

Microbial synthetic epigenetics offers significant opportunities for the design of synthetic biology tools by leveraging reversible gene control mechanisms without altering DNA sequences. However, limited understanding and a lack of technologies for thorough analysis of the mechanisms behind epigenetic modifications have hampered their utilization in biotechnological applications. In this review, we explore advancements in developing epigenetic-based synthetic gene regulatory tools at both transcriptional and post-transcriptional levels. Furthermore, we examine strategies developed to construct epigenetic-based circuits that provide controllable and stable gene regulation, aiming to boost the performance of microbial chassis cells. Finally, we discuss the current challenges and perspectives in the development of synthetic epigenetic tools.

MiR-1 as a Key Epigenetic Regulator in Early Differentiation of Cardiac Sinoatrial Region.

A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. In this study, miR-1 potential role in early cardiac chamber differentiation was analyzed through specific signaling pathways. For this, we performed in chick embryos functional experiments by means of miR-1 microinjections into the posterior cardiac precursors-of both primitive endocardial tubes-committed to sinoatrial region fates. Subsequently, embryos were subjected to whole mount in situ hybridization, immunohistochemistry and RT-qPCR analysis. As a relevant novelty, our results revealed that miR-1 increased Amhc1, Tbx5 and Gata4, while this microRNA diminished Mef2c and Cripto expressions during early differentiation of the cardiac sinoatrial region. Furthermore, we observed in this developmental context that miR-1 upregulated CrabpII and Rarß and downregulated CrabpI, which are three crucial factors in the retinoic acid signaling pathway. Interestingly, we also noticed that miR-1 directly interacted with Hdac4 and Calm1/Calmodulin, as well as with Erk2/Mapk1, which are three key factors actively involved in Mef2c regulation. Our study shows, for the first time, a key role of miR-1 as an epigenetic regulator in the early differentiation of the cardiac sinoatrial region through orchestrating opposite actions between retinoic acid and Mef2c, fundamental to properly assign cardiac cells to their respective heart chambers. A better understanding of those molecular mechanisms modulated by miR-1 will definitely help in fields applied to therapy and cardiac regeneration and repair.

Grafting based DNA methylation alteration of snoRNAs in upland cotton (Gossypium L.)

The effects of grafting in response to various biotic and abiotic stressors have been studied, however, the methylation status of small nucleolar RNA (snoRNA) genes in heterograft and homograft cotton needs investigation. This study was undertaken to determine grafting effects on DNA methylation of snoRNA genes in Upland cotton. Rootstocks used were Pima 3–79 (Gossypium barbadense acc. Pima 3–79) and Texas Marker-1 (G. hirsutum acc. TM-1), representing two different species with different fiber properties, adaptations, and morphologies. The methylation ratio and differently methylated cytosines (DMCs) of 10935 snoRNA genes in mature seeds of heterograft and homograft cotton samples were studied using the whole genome bisulfite sequencing method. Seedling vigor and seed weight were studied to investigate phenotype alterations that might be associated with altered methylation levels among grafts. Statistically significant DMC differences among gene elements of snoRNA genes and between homograft and heterograft cotton samples were identified in the absence of DNA sequence alterations. DNA methylation alterations of snoRNA genes associated with seedling vigor and 100 seed weight. The majority of snoRNA genes showed higher numbers of mCG + mCHG-DMCs with increased methylation levels in heterograft, while there were higher numbers of mCG + mCHG-DMCs with decreased methylation levels in homograft. Since snoRNAs regulate essential genes for plant growth and development and plant adaptation to different habitats or extreme environments, their altered methylation levels should be related with plant physiology.

MiR-1 modulates HDAC4, calmodulin and MAPK1/Erk2 during early atrial differentiation

Abstract Funding Acknowledgements None. Introduction A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. Purpose The aim of this work is to analyze the miR-1 modulation role in cardiac chamber differentiation through specific signaling pathways. Methods By means of microinjections in both primitive endocardial tubes of chick embryo culture, gain- and loss-of-function experiments were performed with premiR-1 and anti-miR-1, respectively. Subsequently, embryos were subjected to whole mount in situ hybridization with Tbx5, Gata4 and AMHC1 probes, as well as immunohistochemistry with Mef2c, HDAC4, Calmodulin/Calm1 and MAPK1/Erk2 antibodies. Also, we carried out RT-qPCR analysis of control and experimental embryos, including CRABPI, CRABPII and retinoic acid receptors (RAR and RXR). Results Our results reveal that miR-1 increases specific atrial gene expression such as Tbx5, Gata4 and AMHC1, while this microRNA diminishes Mef2c expression. Furthermore, we observed that miR-1 upregulates CRABPII and RARß, and downregulates CRABPI, which are three crucial factors in retinoic acid signaling pathway. Interestingly, we also observed that miR-1 actively interacts with HDAC4, Calmodulin and Erk2/MAPK1, key factors involved in Mef2c regulation. Conclusion All these data suggest that miR-1 functions as an epigenetic factor modulating complementary actions performed by retinoic acid and Mef2c, which are required to properly assign cells as sinoatrial precursors.

Role of Epigenetic Modulation in Neurodegenerative Diseases: Implications of Phytochemical Interventions.

Epigenetics defines changes in cell function without involving alterations in DNA sequence. Neuroepigenetics bridges neuroscience and epigenetics by regulating gene expression in the nervous system and its impact on brain function. With the increase in research in recent years, it was observed that alterations in the gene expression did not always originate from changes in the genetic sequence, which has led to understanding the role of epigenetics in neurodegenerative diseases (NDDs) including Alzheimer's disease (AD) and Parkinson's disease (PD). Epigenetic alterations contribute to the aberrant expression of genes involved in neuroinflammation, protein aggregation, and neuronal death. Natural phytochemicals have shown promise as potential therapeutic agents against NDDs because of their antioxidant, anti-inflammatory, and neuroprotective effects in cellular and animal models. For instance, resveratrol (grapes), curcumin (turmeric), and epigallocatechin gallate (EGCG; green tea) exhibit neuroprotective effects through their influence on DNA methylation patterns, histone acetylation, and non-coding RNA expression profiles. Phytochemicals also aid in slowing disease progression, preserving neuronal function, and enhancing cognitive and motor abilities. The present review focuses on various epigenetic modifications involved in the pathology of NDDs, including AD and PD, gene expression regulation related to epigenetic alterations, and the role of specific polyphenols in influencing epigenetic modifications in AD and PD.

Epigenetic and gene therapy in human and veterinary medicine.

Gene therapy is a focus of interest in both human and veterinary medicine, especially in recent years due to the potential applications of CRISPR/Cas9 technology. Another relatively new approach is that of epigenetic therapy, which involves an intervention based on epigenetic marks, including DNA methylation, histone post-translational modifications, and post-transcription modifications of distinct RNAs. The epigenome results from enzymatic reactions, which regulate gene expression without altering DNA sequences. In contrast to conventional CRISP/Cas9 techniques, the recently established methodology of epigenetic editing mediated by the CRISPR/dCas9 system is designed to target specific genes without causing DNA breaks. Both natural epigenetic processes and epigenetic editing regulate gene expression and thereby contribute to maintaining the balance between physiological functions and pathophysiological states. From this perspective, knowledge of specific epigenetic marks has immense potential in both human and veterinary medicine. For instance, the use of epigenetic drugs (chemical compounds with therapeutic potential affecting the epigenome) seems to be promising for the treatment of cancer, metabolic, and infectious diseases. Also, there is evidence that an epigenetic diet (nutrition-like factors affecting epigenome) should be considered as part of a healthy lifestyle and could contribute to the prevention of pathophysiological processes. In summary, epigenetic-based approaches in human and veterinary medicine have increasing significance in targeting aberrant gene expression associated with various diseases. In this case, CRISPR/dCas9, epigenetic targeting, and some epigenetic nutrition factors could contribute to reversing an abnormal epigenetic landscape to a healthy physiological state.

Abstract 7115: Mutational signatures in PDXs for improved understanding of drug response and companion biomarkers identification

Abstract Genomic DNA editing is a continuous process that occurs during the entire cell life span. The type and frequency of these modifications can be related to the physiological or pathological activity of intrinsic mechanisms such as DNA surveillance and repair or to extrinsic events that may induce an alteration of DNA sequence by exposure to agents that directly or indirectly induce accumulations of DNA alterations. In the past few years, large-scale analyses have revealed mutational signatures across human cancer types. These signatures can be used as markers of defective internal processes, such as DNA repair deficiency, or external exposures, such as carcinogens, like tobacco, or genotoxic therapies such as radiation and chemotherapy. Our TumorGraft platform, a collection of 1500 patient-derived xenograft generated from more than 50 different types of cancer, is one of the most comprehensive preclinical oncology platforms worldwide, and aims to recapitulate the variety of the patient population and tumor biology complexity. This platform is currently used to evaluate the efficacy of new drugs, and all our models are very well characterized at the molecular level, including whole transcriptome, proteomics and phospho-proteomics, quantification, and genomic variation calls. This allows accurate selection of models with the molecular characteristics of the target patient population, as well as to identify biomarkers predictive of treatment efficacy. This could eventually lead to the development of companion biomarkers in the clinical setting to improve the identification of patients that will benefit from the treatment and those that should be spared. To maximize the chances of identifying relevant molecular traits associated with tumor response, we have been utilizing the Pharmaco-Pheno-Multiomic (PPMO) integration workflow, a machine learning approach which combines phenotypic and therapeutic response profiles with multiple omics datatypes to generate complex biomarker profiles. To provide additional insights on the molecular characteristics of our tumors, we decided to perform the mutational signatures profiling of our models by using whole exome sequencing data. The results obtained were crossed with patient’s clinical history and showed good correlation between the mutational signatures identified and the treatments received by the patient, in particular for exposure to platinum salts. The addition of PDXs mutational signatures strongly improves our knowledge on these models and confers an important parameter for model selection. Moreover, the integration of mutational signature profiles in the PPMO workflow would make a significant contribution for companion biomarkers identification. Citation Format: Haia Khoury, Stefano Cairo, Mara Gilardi, Michael Ritchie, Gilad Silberberg. Mutational signatures in PDXs for improved understanding of drug response and companion biomarkers identification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7115.

Epigenetic Genome Modifications during Pregnancy: The Impact of Essential Nutritional Supplements on DNA Methylation.

Pregnancy is an extremely stressful period in a pregnant woman's life. Currently, women's awareness of the proper course of pregnancy and its possible complications is constantly growing. Therefore, a significant percentage of women increasingly reach for various dietary supplements during gestation. Some of the most popular substances included in multi-ingredient supplements are folic acid and choline. Those substances are associated with positive effects on fetal intrauterine development and fewer possible pregnancy-associated complications. Recently, more and more attention has been paid to the impacts of specific environmental factors, such as diet, stress, physical activity, etc., on epigenetic modifications, understood as changes occurring in gene expression without the direct alteration of DNA sequences. Substances such as folic acid and choline may participate in epigenetic modifications by acting via a one-carbon cycle, leading to the methyl-group donor formation. Those nutrients may indirectly impact genome phenotype by influencing the process of DNA methylation. This review article presents the current state of knowledge on the use of folic acid and choline supplementation during pregnancy, taking into account their impacts on the maternal-fetal unit and possible pregnancy outcomes, and determining possible mechanisms of action, with particular emphasis on their possible impacts on epigenetic modifications.

CRISPR-DIPOFF: an interpretable deep learning approach for CRISPR Cas-9 off-target prediction.

CRISPR Cas-9 is a groundbreaking genome-editing tool that harnesses bacterial defense systems to alter DNA sequences accurately. This innovative technology holds vast promise in multiple domains like biotechnology, agriculture and medicine. However, such power does not come without its own peril, and one such issue is the potential for unintended modifications (Off-Target), which highlights the need for accurate prediction and mitigation strategies. Though previous studies have demonstrated improvement in Off-Target prediction capability with the application of deep learning, they often struggle with the precision-recall trade-off, limiting their effectiveness and do not provide proper interpretation of the complex decision-making process of their models. To address these limitations, we have thoroughly explored deep learning networks, particularly the recurrent neural network based models, leveraging their established success in handling sequence data. Furthermore, we have employed genetic algorithm for hyperparameter tuning to optimize these models' performance. The results from our experiments demonstrate significant performance improvement compared with the current state-of-the-art in Off-Target prediction, highlighting the efficacy of our approach. Furthermore, leveraging the power of the integrated gradient method, we make an effort to interpret our models resulting in a detailed analysis and understanding of the underlying factors that contribute to Off-Target predictions, in particular the presence of two sub-regions in the seed region of single guide RNA which extends the established biological hypothesis of Off-Target effects. To the best of our knowledge, our model can be considered as the first model combining high efficacy, interpretability and a desirable balance between precision and recall.

DNA Sequence Control of Enzyme Filamentation and Activation of the SgrAI Endonuclease.

Enzyme polymerization (also known as filamentation) has emerged as a new layer of enzyme regulation. SgrAI is a sequence-dependent DNA endonuclease that forms polymeric filaments with enhanced DNA cleavage activity as well as altered DNA sequence specificity. To better understand this unusual regulatory mechanism, full global kinetic modeling of the reaction pathway, including the enzyme filamentation steps, has been undertaken. Prior work with the primary DNA recognition sequence cleaved by SgrAI has shown how the kinetic rate constants of each reaction step are tuned to maximize activation and DNA cleavage while minimizing the extent of DNA cleavage to the host genome. In the current work, we expand on our prior study by now including DNA cleavage of a secondary recognition sequence, to understand how the sequence of the bound DNA modulates filamentation and activation of SgrAI. The work shows that an allosteric equilibrium between low and high activity states is modulated by the sequence of bound DNA, with primary sequences more prone to activation and filament formation, while SgrAI bound to secondary recognition sequences favor the low (and nonfilamenting) state by up to 40-fold. In addition, the degree of methylation of secondary sequences in the host organism, Streptomyces griseus, is now reported for the first time and shows that as predicted, these sequences are left unprotected from the SgrAI endonuclease making sequence specificity critical in this unusual filament-forming enzyme.

MAJOR DEPRESSIVE DISORDER, ENVIRONMENTAL FACTORS AND EPIGENETICS

New insights in the epigenetics have declared depression as genetic malady. For psychiatric disorders evaluation of epigenetic basis influenced by environment insults showed deeper understanding of complex multifactorial psychiatric disorder like Major depressive disorder (MDD). The World Health Organization (2008 report) has ranked MDD globally as the third cause of burden of diseases and predicted it to be the number one by 2030. Eight hallmarks of insults that lead to MDD are contaminated air, soil, food/water, ecological stressors, chemicals in households, occupational hazards as well as food/diet linked to absence of essential nutrients. Epigenetics, according to National Human Genome Research Institute, refers to changes in gene function causing their activation or deactivation without any alteration in DNA sequence. Epigenetics include histone modifications, DNA methylations, miRNAs and lncRNAs. Hypermethylation of serotonin transporter gene has been consistently found in loci encoding brain derived neurotrophic factors BDNF and SLC6A4. During pregnancy fetal epigenetic reprogramming may occur due to maternal stress and nutritional restriction. Increased cortisol or malnutrition in mothers, down-regulate cortisol enzyme, decreasing its expression in fetal cortex, making these children 4 times more at risk to stress later in life. Histones modifications including methylation and acetylation at lysine moiety during posttranslational modifications, affect neurons of CNS significantly leading to pathophysiology of MDD. Dysregulation of miRNAs and lncRNAs cause negative neural plasticity, stress responses, neurotrophic factors expression, neuroinflammation, neurotransmission, HPA axis, neurogenesis and gliogenesis and neural stem cell maintenance. Among epigenetic multifactorial disorders, psychiatric ailments have received prominence in etiology than other diseases.

Epigenetic Regulation of Neuroinflammation in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease and clinically manifests with cognitive decline and behavioral disabilities. Over the past years, mounting studies have demonstrated that the inflammatory response plays a key role in the onset and development of AD, and neuroinflammation has been proposed as the third major pathological driving factor of AD, ranking after the two well-known core pathologies, amyloid β (Aβ) deposits and neurofibrillary tangles (NFTs). Epigenetic mechanisms, referring to heritable changes in gene expression independent of DNA sequence alterations, are crucial regulators of neuroinflammation which have emerged as potential therapeutic targets for AD. Upon regulation of transcriptional repression or activation, epigenetic modification profiles are closely involved in inflammatory gene expression and signaling pathways of neuronal differentiation and cognitive function in central nervous system disorders. In this review, we summarize the current knowledge about epigenetic control mechanisms with a focus on DNA and histone modifications involved in the regulation of inflammatory genes and signaling pathways in AD, and the inhibitors under clinical assessment are also discussed.

Review of the association between non-coding RNAs and environmental exposure

Disease development is a consequence of the combination of genetic and environmental factors. Epigenetics can regulate gene expression without altering DNA sequence. There are different types of epigenetic regulation, including DNA methylation, histone modification and non-coding RNAs. Research has shown epigenetic regulation plays an essential role in environmental exposure and disease development. The role of DNA methylation and histone modification is well characterized so far. While the importance of non-coding RNA in disease development has gained more attention recently, the elucidation of the exposure-non coding RNA-disease pathway is still under much investigation. This review aims to provide a general review of ncRNA functions, focusing on research progress highlighting the association between a variety of exposure and non-coding RNAs and the hope of demonstrating how non-coding RNA can serve as biomarkers for preventive and therapeutic goals upon environmental exposure.

Epigenome-Driven Strategies for Personalized Cancer Immunotherapy.

Fighting cancer remains one of the greatest challenges for science in the 21st century. Advances in immunotherapy against different types of cancer have greatly contributed to the treatment, remission, and cure of patients. In this context, knowledge of epigenetic phenomena, their relationship with tumor cells and how the immune system can be epigenetically modulated represent some of the greatest advances in the development of anticancer therapies. Epigenetics is a rapidly growing field that studies how environmental factors can affect gene expression without altering DNA sequence. Epigenomic changes include DNA methylation, histone modifications, and non-coding RNA regulation, which impact cellular function. Epigenetics has shown promise in developing cancer therapies, such as immunotherapy, which aims to stimulate the immune system to attack cancer cells. For example, PD-1 and PD-L1 are biomarkers that regulate the immune response to cancer cells and recent studies have shown that epigenetic modifications can affect their expression, potentially influencing the efficacy of immunotherapy. New therapies targeting epigenetic modifications, such as histone deacetylases and DNA methyltransferases, are being developed for cancer treatment, and some have shown promise in preclinical studies and clinical trials. With growing understanding of epigenetic regulation, we can expect more personalized and effective cancer immunotherapies in the future. This review highlights key advances in the use of epigenetic and epigenomic tools and modern immuno-oncology strategies to treat several types of tumors.

Methylation-directed regulatory networks determine enhancing and silencing of mutation disease driver genes and explain inter-patient expression variation

BackgroundCommon diseases manifest differentially between patients, but the genetic origin of this variation remains unclear. To explore possible involvement of gene transcriptional-variation, we produce a DNA methylation-oriented, driver-gene-wide dataset of regulatory elements in human glioblastomas and study their effect on inter-patient gene expression variation.ResultsIn 175 of 177 analyzed gene regulatory domains, transcriptional enhancers and silencers are intermixed. Under experimental conditions, DNA methylation induces enhancers to alter their enhancing effects or convert into silencers, while silencers are affected inversely. High-resolution mapping of the association between DNA methylation and gene expression in intact genomes reveals methylation-related regulatory units (average size = 915.1 base-pairs). Upon increased methylation of these units, their target-genes either increased or decreased in expression. Gene-enhancing and silencing units constitute cis-regulatory networks of genes. Mathematical modeling of the networks highlights indicative methylation sites, which signified the effect of key regulatory units, and add up to make the overall transcriptional effect of the network. Methylation variation in these sites effectively describe inter-patient expression variation and, compared with DNA sequence-alterations, appears as a major contributor of gene-expression variation among glioblastoma patients.ConclusionsWe describe complex cis-regulatory networks, which determine gene expression by summing the effects of positive and negative transcriptional inputs. In these networks, DNA methylation induces both enhancing and silencing effects, depending on the context. The revealed mechanism sheds light on the regulatory role of DNA methylation, explains inter-individual gene-expression variation, and opens the way for monitoring the driving forces behind deferential courses of cancer and other diseases.

Dissecting molecular evolution of class 1 integron gene cassettes and identifying their bacterial hosts in suburban creeks via epicPCR.

Our study aimed to sequence class 1 integrons in uncultured environmental bacterial cells in freshwater from suburban creeks and uncover the taxonomy of their bacterial hosts. We also aimed to characterize integron gene cassettes with altered DNA sequences relative to those from databases or literature and identify key signatures of their molecular evolution. We applied a single-cell fusion PCR-based technique-emulsion, paired isolation and concatenation PCR (epicPCR)-to link class 1 integron gene cassette arrays to the phylogenetic markers of their bacterial hosts. The levels of streptomycin resistance conferred by the WT and altered aadA5 and aadA11 gene cassettes that encode aminoglycoside (3″) adenylyltransferases were experimentally quantified in an Escherichia coli host. Class 1 integron gene cassette arrays were detected in Alphaproteobacteria and Gammaproteobacteria hosts. A subset of three gene cassettes displayed signatures of molecular evolution, namely the gain of a regulatory 5'-untranslated region (5'-UTR), the loss of attC recombination sites between adjacent gene cassettes, and the invasion of a 5'-UTR by an IS element. Notably, our experimental testing of a novel variant of the aadA11 gene cassette demonstrated that gaining the observed 5'-UTR contributed to a 3-fold increase in the MIC of streptomycin relative to the ancestral reference gene cassette in E. coli. Dissecting the observed signatures of molecular evolution of class 1 integrons allowed us to explain their effects on antibiotic resistance phenotypes, while identifying their bacterial hosts enabled us to make better inferences on the likely origins of novel gene cassettes and IS that invade known gene cassettes.

Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents.

Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to their inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances in which vaccination is not accessible or in individuals with compromised immune systems, drugs can provide additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Moreover, targeting host factors allows us to develop compounds that are effective against different viral variants as well as against newly emerging virus strains. In recent years, the globe has experienced climate change, which may contribute to the emergence and spread of infectious diseases through a variety of factors. Warmer temperatures and changing precipitation patterns can increase the geographic range of disease-carrying vectors, increasing the risk of diseases spreading to new areas. Climate change may also affect vector behavior, leading to a longer breeding season and more breeding sites for disease vectors. Climate change may also disrupt ecosystems, bringing humans closer to wildlife that transmits zoonotic diseases. All the above factors may accelerate the emergence of new viral epidemics. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds, including those with anti-viral activity. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Interest in herbal antiviral products has increased. More than 50% of approved drugs originate from herbal sources. Plant-derived compounds offer diverse structures and bioactive molecules that are candidates for new drug development. Combining these therapies with conventional drugs could improve patient outcomes. Epigenetics modifications in the genome can affect gene expression without altering DNA sequences. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses recruit cellular epitranscriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we explore the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing their modulation processes and anti-viral effects on DNA and RNA viruses, as well as addressing future research objectives in this rapidly emerging field.