[The impact of today's environment on allergies: can we take action?] / Incidence de l'environnement actuel sur les allergies : peut-on agir ?

Allergic diseases have risen sharply in recent decades. After some epidemiological data, we take a look at the various hypotheses explaining this allergy "epidemic". Changes in our environment, such as pollution, are a source of climate change and an increase in allergic diseases through inflammation of epithelial barriers. Allergy prevention, a public health emergency, relies on environmental actions at both individual and collective levels.

43rd International Asilomar Chromatin, Chromosomes, and Epigenetics Conference.

The 43rd Asilomar Chromatin, Chromosomes, and Epigenetics Conference was held in an entirely online format from 9 to 11 December 2021. The conference enabled presenters at various career stages to share promising new findings, and presentations covered modern chromatin research across an array of model systems. Topics ranged from the fundamental principles of nuclear organization and transcription regulation to key mechanisms underlying human disease. The meeting featured five keynote speakers from diverse backgrounds and was organized by Juan Ausió, University of Victoria (British Columbia, Canada), James Davie, University of Manitoba (Manitoba, Canada), Philippe T. Georgel, Marshall University (West Virginia, USA), Michael Goldman, San Francisco State University (California, USA), LeAnn Howe, The University of British Columbia (British Columbia, Canada), Jennifer A. Mitchell, University of Toronto (Ontario, Canada), and Sally G. Pasion, San Francisco State University (California, USA).

Substitution of histone H3 arginine 72 to alanine leads to the deregulation of isoleucine biosynthesis in the budding yeast Saccharomyces cerevisiae.

Histone residues play an essential role in the regulation of various biological processes. In the present study, we utilized the H3/H4 histone mutant library to probe the functional aspects of histone residues in amino acid biosynthesis. We found that the histone residue H3R72 plays a crucial role in the regulation of isoleucine biosynthesis. Substitution of the arginine residue (H3R72) of histone H3 to alanine (H3R72A) renders yeast cells unable to grow in minimal medium. Histone mutant H3R72A requires external supplementation of either isoleucine, serine, or threonine for growth in minimal medium. We also observed that the H3R72 residue and leucine amino acid in synthetic complete medium might play a crucial role in determining the intake of isoleucine and threonine in yeast. Furthermore, gene deletion analysis of ILV1 and CHA1 in the H3R72A mutant confirmed that isoleucine is the sole requirement for growth in minimal medium. Altogether, we have identified that histone H3R72 residue may be crucial for yeast growth in minimal medium by regulating isoleucine biosynthesis through the Ilv1 enzyme in the budding yeast Saccharomyces cerevisiae.

Introgressed DNA within a Zea mays near-isogenic line displays lower levels of 24nt sRNA expression than the homologous region from the recurrent parent.

Near-isogenic lines (NILs) are classical genetic tools used to dissect the actions of an allele when placed in a uniform genetic background. Although the goal of NIL creation is to examine the effects of a single allele in isolation, DNA linked to the allele is invariably retained and can confound any allele-specific effects. In addition to genetic variation, highly polymorphic species such as Zea mays will contain introgressed polymorphisms encompassing transposable elements (TEs) and the cis-acting small RNA (sRNA) that represses them. Through transcriptomics, we described the differences in sRNA and TE transcriptional expression between a W22-derived introgression and its homologous B73 region. As anticipated, many differences in sRNA expression were observed. Unexpectedly, however, 24nt sRNA expression over the introgressed region was low overall compared to both the homologous B73 region and the rest of the genome. Across the introgression, low sRNA expression was accompanied by increased TE transcription. Possible explanations for the observed trends in sRNA and TE expression across the introgression region are discussed. These findings support the notion that any introgressed allele is in an epigenetic environment distinct from that found at the allele from the recurrent parent. Additionally, these results suggest that further study of sRNA expression levels during the introgression process is warranted.

Epigenetic mechanisms influencing COVID-19.

The COVID-19 pandemic is one of the most significant public health threats in recent history and has impacted the lives of almost everyone worldwide. Epigenetic mechanisms contribute to many aspects of the SARS-CoV-2 replication cycle, including expression levels of viral receptor ACE2, expression of cytokine genes as part of the host immune response, and the implication of various histone modifications in several aspects of COVID-19. SARS-CoV-2 proteins physically associate with many different host proteins over the course of infection, and notably there are several interactions between viral proteins and epigenetic enzymes such as HDACs and bromodomain-containing proteins as shown by correlation-based studies. The many contributions of epigenetic mechanisms to the viral life cycle and the host immune response to infection have resulted in epigenetic factors being identified as emerging biomarkers for COVID-19, and project epigenetic modifiers as promising therapeutic targets to combat COVID-19. This review article highlights the major epigenetic pathways at play during COVID-19 disease and discusses ongoing clinical trials that will hopefully contribute to slowing the spread of SARS-CoV-2.

Gut microbiome-mediated epigenetic regulation of brain disorder and application of machine learning for multi-omics data analysis.

The gut-brain axis (GBA) is a biochemical link that connects the central nervous system (CNS) and enteric nervous system (ENS). Clinical and experimental evidence suggests gut microbiota as a key regulator of the GBA. Microbes living in the gut not only interact locally with intestinal cells and the ENS but have also been found to modulate the CNS through neuroendocrine and metabolic pathways. Studies have also explored the involvement of gut microbiota dysbiosis in depression, anxiety, autism, stroke, and pathophysiology of other neurodegenerative diseases. Recent reports suggest that microbe-derived metabolites can influence host metabolism by acting as epigenetic regulators. Butyrate, an intestinal bacterial metabolite, is a known histone deacetylase inhibitor that has shown to improve learning and memory in animal models. Due to high disease variability amongst the population, a multi-omics approach that utilizes artificial intelligence and machine learning to analyze and integrate omics data is necessary to better understand the role of the GBA in pathogenesis of neurological disorders, to generate predictive models, and to develop precise and personalized therapeutics. This review examines our current understanding of epigenetic regulation of the GBA and proposes a framework to integrate multi-omics data for prediction, prevention, and development of precision health approaches to treat brain disorders.

The chicken model organism for epigenomic research.

The chicken model organism has advanced the areas of developmental biology, virology, immunology, oncology, epigenetic regulation of gene expression, conservation biology, and genomics of domestication. Further, the chicken model organism has aided in our understanding of human disease. Through the recent advances in high-throughput sequencing and bioinformatic tools, researchers have successfully identified sequences in the chicken genome that have human orthologs, improving mammalian genome annotation. In this review, we highlight the importance of chicken as an animal model in basic and pre-clinical research. We will present the importance of chicken in poultry epigenetics and in genomic studies that trace back to their ancestor, the last link between human and chicken in the tree of life. There are still many genes of unknown function in the chicken genome yet to be characterized. By taking advantage of recent sequencing technologies, it is possible to gain further insight into the chicken epigenome.

The treatment of SARS-CoV2 with antivirals and mitigation of the cytokine storm syndrome: the role of gene expression.

In the absence of a vaccine, the treatment of SARS-CoV2 has focused on eliminating the virus with antivirals or mitigating the cytokine storm syndrome (CSS) that leads to the most common cause of death: respiratory failure. Herein we discuss the mechanisms of antiviral treatments for SARS-CoV2 and treatment strategies for the CSS. Antivirals that have shown in vitro activity against SARS-CoV2, or the closely related SARS-CoV1 and MERS-CoV, are compared on the enzymatic level and by potency in cells. For treatment of the CSS, we discuss medications that reduce the effects or expression of cytokines involved in the CSS with an emphasis on those that reduce IL-6 because of its central role in the development of the CSS. We show that some of the medications covered influence the activity or expression of enzymes involved in epigenetic processes and specifically those that add or remove modifications to histones or DNA. Where available, the latest clinical data showing the efficacy of the medications is presented. With respect to their mechanisms, we explain why some medications are successful, why others have failed, and why some untested medications may yet prove useful.

Epigenetic regulation of ACE2, the receptor of the SARS-CoV-2 virus1.

The angiotensin-converting enzyme 2 (ACE2) is the receptor for the three coronaviruses HCoV-NL63, SARS-CoV, and SARS-CoV-2. ACE2 is involved in the regulation of the renin-angiotensin system and blood pressure. ACE2 is also involved in the regulation of several signaling pathways, including integrin signaling. ACE2 expression is regulated transcriptionally and post-transcriptionally. The expression of the gene is regulated by two promoters, with usage varying among tissues. ACE2 expression is greatest in the small intestine, kidney, and heart and detectable in a variety of tissues and cell types. Herein we review the chemical and mechanical signal transduction pathways regulating the expression of the ACE2 gene and the epigenetic/chromatin features of the expressed gene.

The impact of sex and gender on heart-brain axis dysfunction: current concepts and novel perspectives.

The heart-brain axis (HBA) recapitulates all the circuits that regulate bidirectional flow of communication between heart and brain. Several mechanisms may underlie the interdependent relationship involving heterogeneous tissues at rest and during specific target organ injury such as myocardial infarction, heart failure, arrhythmia, stroke, mood disorders, or dementia. In-depth translational studies of the HBA dysfunction under single-organ injury should include both male and female animals to develop sex- and gender-oriented prevention, diagnosis, and treatment strategies. Indeed, sex and gender are determining factors as females and males exhibit significant differences in terms of susceptibility to risk factors, age of onset, severity of symptoms, and outcome. Despite most studies having focused on the male population, we have conducted a careful appraisal of the literature investigating HBA in females. In particular, we have (i) analyzed sex-related heart and brain illnesses, (ii) recapitulated the most significant studies simultaneously conducted on cardio- and cerebro-vascular systems in female populations, and (iii) hypothesized future perspectives for the development of a gender-based approach to HBA dysfunction. Although sex- and gender-oriented research is at its infancy, the impact of sex on HBA dysfunction is opening unexpected new avenues for managing the health of female subjects exposed to risk of lifestyle multi-organ disease.

Hyperhomocysteinemia: an instigating factor for periodontal disease.

Hyperhomocysteinemia (HHcy) affects bone remodeling, since a destructive process in cortical alveolar bone has been linked to it; however, the mechanism remains at large. HHcy increases proinflammatory cytokines viz. TNF-α, IL-1b, IL-6, and IL-8 that leads to a cascade that negatively impacts methionine metabolism and homocysteine cycling. Further, chronic inflammation decreases vitamins B12, B6, and folic acid that are required for methionine homocysteine homeostasis. This study aims to investigate a HHcy mouse model (cystathionine ß-synthase deficient, CBS+/-) for studying the potential pathophysiological changes, if any, in the periodontium (gingiva, periodontal ligament, cement, and alveolar bone). We compared the periodontium side-by-side in the CBS+/- model with that of the wild-type (C57BL/6J) mice. Histology and histomorphometry of the mandibular bone along with gene expression analyses were carried out. Also, proangiogenic proteins and metalloproteinases were studied. To our knowledge, this research shows, for the first time, a direct connection between periodontal disease during CBS deficiency, thereby suggesting the existence of disease drivers during the hyperhomocysteinemic condition. Our findings offer opportunities to develop diagnostics/therapeutics for people who suffer from chronic metabolic disorders like HHcy.

DNA methylation and regulation of DNA methyltransferases in a freeze-tolerant vertebrate.

The wood frog is one of the few freeze-tolerance vertebrates. This is accomplished in part by the accumulation of cryoprotectant glucose, metabolic rate depression, and stress response activation. These may be achieved by mechanisms such as DNA methylation, which is typically associated with transcriptional repression. Hyperglycemia is also associated with modifications to epigenetic profiles, indicating an additional role that the high levels of glucose play in freeze tolerance. We sought to determine whether DNA methylation is affected during freezing exposure, and whether this is due to the wood frog's response to hyperglycemia. We examined global DNA methylation and DNA methyltransferases (DNMTs) in the liver and muscle of frozen and glucose-loaded wood frogs. The results showed that levels of 5-methylcytosine (5mC) increased in the muscle, suggesting elevated DNA methylation during freezing. DNMT activities also decreased in muscle during thawing, glucose loading, and in vitro glucose experiments. Liver DNMT activities were similar to muscle; however, a varied response to DNMT levels and a decrease in 5mC highlight the metabolic role the liver plays during freezing. Glucose was also shown to decrease DNMT activity levels in the wood frog, in vitro, elucidating a potentially novel regulatory mechanism. Together these results suggest an interplay between freeze tolerance and hyperglycemic regulation of DNA methylation.

Beyond the genome: challenges and potential for epigenetics-driven therapeutic approaches in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease of the cardiopulmonary system caused by the narrowing of the pulmonary arteries, leading to increased vascular resistance and pressure. This leads to right ventricle remodeling, dysfunction, and eventually, death. While conventional therapies have largely focused on targeting vasodilation, other pathological features of PAH including aberrant inflammation, mitochondrial dynamics, cell proliferation, and migration have not been well explored. Thus, despite some recent improvements in PAH treatment, the life expectancy and quality of life for patients with PAH remains poor. Showing many similarities to cancers, PAH is characterized by increased pulmonary arterial smooth muscle cell proliferation, decreased apoptotic signaling pathways, and changes in metabolism. The recent successes of therapies targeting epigenetic modifiers for the treatment of cancer has prompted epigenetic research in PAH, revealing many new potential therapeutic targets. In this minireview we discuss the emergence of epigenetic dysregulation in PAH and highlight epigenetic-targeting compounds that may be effective for the treatment of PAH.

The impact of epigenetics on cardiovascular disease.

Mortality and morbidity from cardiovascular diseases (CVDs) represents a huge burden to society. It is recognized that environmental factors and individual lifestyles play important roles in disease susceptibility, but the link between these external risk factors and our genetics has been unclear. However, the discovery of sequence-independent heritable DNA changes (epigenetics) have helped us to explain the link between genes and the environment. Multiple diverse epigenetic processes, including DNA methylation, histone modification, and the expression of non-coding RNA molecules affect the expression of genes that produce important changes in cellular differentiation and function, influencing the health and adaptability of the organism. CVDs such as congenital heart disease, cardiomyopathy, heart failure, cardiac fibrosis, hypertension, and atherosclerosis are now being viewed as much more complex and dynamic disorders. The role of epigenetics in these and other CVDs is currently under intense scrutiny, and we can expect important insights to emerge, including novel biomarkers and new approaches to enable precision medicine. This review summarizes the recent advances in our understanding of the role of epigenetics in CVD.

A novel understanding of global DNA methylation in bobcat (Lynx rufus).

Epigenetic mechanisms may provide a novel prospective of bobcat (Lynx rufus) adaptation to habitat loss/fragmentation. Previous research has focused on bobcat behavior and genetics, but epigenetics has not been studied in bobcat. The aim of this study was to determine the quantity of global DNA methylation in the liver of 30 bobcats. DNA was extracted from liver samples obtained from the Vermont Fish and Wildlife Department. The percent of global DNA methylation was quantified and calculated using the MethylFlashTM Methylated DNA 5-mC Quantification Kit from Epigentek (Farmingdale, NY, USA). Age, sex, and carcass weight data were collected at sampling and analyzed with percent of global DNA methylation. Global DNA methylation was found to range from 0.46% to 2.76%. Age ranged from <1 to 12 years old and weight ranged from 3.18 to 13.61 kg. Further analysis of differential methylation may provide insight into novel means of bobcat conservation within different regions of Vermont. These results reinforce the need for genome-wide epigenetic studies in conservation biology.

Does variable epigenetic inheritance fuel plant evolution?

Epigenetic changes influence gene expression and contribute to the modulation of biological processes in response to the environment. Transgenerational epigenetic changes in gene expression have been described in many eukaryotes. However, plants appear to have a stronger propensity for inheriting novel epialleles. This mini-review discusses how plant traits, such as meristematic growth, totipotency, and incomplete epigenetic erasure in gametes promote epiallele inheritance. Additionally, we highlight how plant biology may be inherently tailored to reap the benefits of epigenetic metastability. Importantly, environmentally triggered small RNA expression and subsequent epigenetic changes may allow immobile plants to adapt themselves, and possibly their progeny, to thrive in local environments. The change of epigenetic states through the passage of generations has ramifications for evolution in the natural and agricultural world. In populations containing little genetic diversity, such as elite crop germplasm or habitually self-reproducing species, epigenetics may provide an important source of heritable phenotypic variation. Basic understanding of the processes that direct epigenetic shifts in the genome may allow for breeding or bioengineering for improved plant traits that do not require changes to DNA sequence.

40th International Asilomar Chromatin, Chromosomes, and Epigenetics Conference.

The 40th International Asilomar Chromatin, Chromosomes, and Epigenetics Conference was held in the Asilomar Conference Grounds, Pacific Grove, California, USA, on 6-9 December 2018. The organizing committee consisted of established scientists in the fields of chromatin and epigenetics: Sally Pasion and Michael Goldman from the Biology Department, San Francisco State University, California, USA; Philippe Georgel from the Department of Biological Sciences, Marshal University, West Virginia, USA; Juan Ausió from the Department of Biochemistry and Microbiology, University of Victoria, British Columbia, Canada; and Christopher Eskiw from the Department of Biochemistry, University of Saskatchewan, Saskatchewan, Canada. The meeting had two keynote speakers: Jessica Tyler and Jennifer Mitchell, and it covered topics on transcription, replication and repair, epigenetics, cell differentiation and disease, telomeres, and centromeres and it had two sessions devoted to nuclear and genomic organization. It encompassed the enthusiastic presentations of excellent trainees within the breathtaking natural setting of Pacific Grove.

Coordinated Tcf7l2 regulation in a mouse model implicates Wnt signaling in fetal alcohol spectrum disorders.

Mouse models of fetal alcohol spectrum disorders (FASD) have repeatedly identified genes with long-term changes in expression, DNA methylation, noncoding RNA, and histone modifications in response to neurodevelopmental alcohol exposure. Articulation of FASD is achieved via alcohol's effect on gene expression, likely involving epigenetic regulation. The list of genes affected is large and heterogeneous, depending on experimental protocol. We present reanalysis and synthesis of results highlighting the Wnt transcription factor 7 like 2 (Tcf7l2) gene as uniquely compatible with hippocampal DNA methylation, histone modifications, and gene expression changes in a coordinated response to neurodevelopmental alcohol exposure. We data-mined the literature for Tcf7l2 alterations in response to prenatal alcohol exposure. Four studies identified changes in brain Tcf7l2 expression in different FASD models. Further, we performed an in silico TCF7L2 binding site analysis for FASD mouse model data sets. Seven of these published gene lists were significantly enriched for TCF7L2 binding, indicating potential functional relationships. Finally, TCF7L2 is involved in regulation of hundreds of genes, with a role in brain development, myelination, and neuronal function. Tcf7l2 may be involved in neurological defects associated with alcohol exposure via dysregulation of many genes through Wnt signaling. Further functional work is warranted to validate this model for FASD.

How alcohol drinking affects our genes: an epigenetic point of view.

This work highlights recent studies in epigenetic mechanisms that play a role in alcoholism, which is a complex multifactorial disorder. There is a large body of evidence showing that alcohol can modify gene expression through epigenetic processes, namely DNA methylation and nucleosomal remodeling via histone modifications. In that regard, chronic exposure to ethanol modifies DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol-mediated chromatin remodeling in the brain promotes the transition from use to abuse and addiction. Unravelling the multiplex pattern of molecular modifications induced by ethanol could support the development of new therapies for alcoholism and drug addiction targeting epigenetic processes.

DNA methylation of NR3c1 in infancy: Associations between maternal caregiving and infant sex.

Caregivers play a critical role in scaffolding infant stress reactivity and regulation, but the mechanisms by which this scaffolding occurs is unclear. Animal models strongly suggest that epigenetic processes, such as DNA methylation, are sensitive to caregiving behaviors and, in turn, offspring stress reactivity. We examined the direct effects of caregiving behaviors on DNA methylation in infants and infant stress reactivity. Infants and mothers (N = 128) were assessed during a free play when infants were 5 months old. Maternal responsiveness and appropriate touch were coded. and infant buccal epithelial cells were sampled to assess for DNA methylation of the glucocorticoid receptor gene, NR3c1 exon 1F. Infant cortisol reactivity was assessed in response to the still-face paradigm. Greater levels of maternal responsiveness and appropriate touch were related to less DNA methylation of specific regions in NR3c1 exon 1F, but only for females. There was no association with maternal responsiveness and appropriate touch or DNA methylation of NR3c1 exon 1F on prestress cortisol or cortisol reactivity. Our results are discussed in relation to programming models that implicate maternal care as an important factor in programing infant stress reactivity.

Los cuidadores juegan un papel esencial en el andamiaje de la reactividad y regulación del estrés infantil pero los mecanismos por medio de los cuales aparece este andamiaje no están claros. Los modelos animales fuertemente sugieren que los procesos epigenéticos, tales como la metilación del ADN, son sensibles a los comportamientos de prestaciones de cuidado y por consiguiente a la reactividad al estrés por parte de los hijos. Examinamos los efectos directos que los comportamientos de prestaciones de cuidado tienen sobre la metilación de ADN en infantes y, por consiguiente, la reactividad del estrés infantil. Los infantes y sus madres (N = 128) fueron evaluados durante una sesión de juego libre cuando los infantes tenían 5 meses de edad. Se codificó la sensibilidad materna y la apropiada forma de tocar y se obtuvo muestra de las células epiteliales bucales del infante para analizar la metilación de ADN del gen receptor glucocorticoide, NR3c1, exón 1F. Se evaluó la reactividad del infante al cortisol como respuesta al paradigma de la cara quieta. Niveles mayores de sensibilidad materna y apropiada forma de tocar se relacionaron con menos metilación de ADN de regiones específicas en NR3c1 exón 1F, aunque sólo en las niñas. No se presentó ninguna asociación con la sensibilidad materna y la apropiada forma de tocar, o metilación de ADN de NR3c1 exón 1F en el cortisol pre-estrés o la reactividad del cortisol. Nuestros resultados se discuten en relación con modelos de programación que implican cuidado materno como un importante factor en la programación de la reactividad del estrés del infante.

Les personnes prenant soin des enfants jouent un rôle critique dans l'échafaudage de la réaction au stress du nourrisson et la régulation mais les mécanismes selon lesquels cet échafaudage se bâtit ne sont pas clairs. Les modèles animaux suggèrent fortement que des processus épigénétiques, comme la méthylation de l'ADN, sont sensibles au comportements de qui prend soin d'eux et en conséquence déclenchent un réaction au stress. Nous avons examiné les effets directs des comportements soignants sur la méthylation de l'ADN chez les bébés, en ensuite sur la réaction au stress du nourrisson. Des nourrissons et leurs mères (N = 128) ont été évalués au moyen d'un jeu libre quand les bébés avaient 5 mois d'âge. La réaction maternelle et le toucher approprié ont été codés et des cellules épithéliales buccales du bébé ont été prélevées afin d'évaluer la méthylation de l'ADN du gène récepteur glucocorticoïde, le NR3c1 exon 1F. La réaction du cortisol du bébé a été évaluée en réponse au paradigme du visage immuable. Des niveaux plus élevés de réaction maternelle et de toucher approprié étaient liés à une méthylation de l'ADN des régions spécifiques de NR3c1 exon 1F moindre, mais seulement chez les filles. On n'a trouvé aucun lien avec la réaction maternelle et le toucher approprié ou de méthylation NR3c1 exon 1F de l'ADN sur le cortisol pré-test ou de réaction du cortisol. Nos résultats sont discutés en relation aux modèles de programme qui impliquent que le soin maternel en tant que facteur important dans la programmation de la réaction au stress du bébé.