Genetic Expression Alterations Research Articles

Long-Term Epigenetic Regulation of Foxo3 Expression in Neonatal Valproate-Exposed Rat Hippocampus with Sex-Related Differences.

Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been proposed to induce epigenetic changes during neurodevelopment, but the specific alterations in genetic expression underlying ASD-like behavioral changes remain unclear. We used qPCR-based gene expression and epigenetics tools and Western blotting in the hippocampi of neonatal valproic acid-exposed animals at 4 weeks of age and conducted the social interaction test to detect behavioral changes. Significant alterations in gene expression were observed in males, particularly concerning mRNA expression of Foxo3, which was significantly associated with behavioral changes. Moreover, notable differences were observed in H3K27ac chromatin immunoprecipitation, quantitative PCR (ChIP-qPCR), and methylation-sensitive restriction enzyme-based qPCR targeting the Foxo3 gene promoter region. These findings provide evidence that epigenetically regulated hippocampal Foxo3 expression may influence social interaction-related behavioral changes. Furthermore, identifying sex-specific gene expression and epigenetic changes in this model may elucidate the sex disparity observed in autism spectrum disorder prevalence.

Nanomaterial-induced Changes in Plant Physiology and Genetics: Implications for Crop Improvement Strategies

The utilization of nanomaterials in agriculture has gained significant attention due to their potential to induce changes in plant physiology and genetics, thereby offering new avenues for enhancing crop improvement strategies. This paper delves into the intricate interplay between nanomaterials and plants, shedding light on their molecular mechanisms of uptake and interaction. It explores the physiological responses that ensue following nanomaterial exposure, unraveling the intricate network of signaling pathways and stress responses. Moreover, the paper delves into the alterations in genetic expression triggered by nanomaterials, providing insights into the underlying regulatory mechanisms. The influence of epigenetic factors and potential transgenerational effects further accentuates the complexity of these interactions. Underpinning this understanding, the paper discusses the prospects of harnessing nanomaterial-induced changes to enhance crop traits. It investigates how these changes can be employed to boost crop resilience, nutrient uptake, and stress tolerance. The integration of nanomaterial-induced alterations into breeding and genetic modification strategies offers a promising approach for developing improved crop varieties. Ultimately, this comprehensive exploration of nanomaterial-induced changes in plant physiology and genetics highlights their far-reaching implications for revolutionizing crop improvement strategies in the face of evolving agricultural challenges.

Mycoviruses: trends in plant-fungus-mycovirus interactions and ‘biocontrol’ prospects in agriculture and the environment

Mycoviruses are cosmopolitan in plants, animals, fungi, bacteria, in soils, and water. There is a scarcity of information about them, which necessitated this review to provide some leads on where research should focus. Mycoviruses are able to persist in disparate types of hosts by utilizing diverse measures. They may engage either parasitic, pathogenic, or mutualistic tendencies. Mycoviruses employ many existential strategies that can be utilized by man. Hypovirulence may be induced in fungal hosts by mycoviruses via RNA silencing, alteration of genetic expression, and disruption of the transcriptome. Mycoviruses interact with killer phenotypes of yeasts and Ustilago spp. and proffer advantages to these fungi. Mycovirus interaction with some plants result in provision of thermal tolerance to plants. Based on their mode of microbe destruction mycoviruses may be used for waste disposal and termination of some life processes. For instance, grazer viruses completely oxidize the organic content of their host into carbon dioxide and inorganic nutrients, while lytic viruses release the organic material from their hosts without modification. Viruses may be utilized to facilitate the exchange of genetic material from one host to another. However, pathogenic mycoviruses exist especially in mushrooms.

Exposed to Sulfamethoxazole induced hepatic lipid metabolism disorder and intestinal microbiota changes on zebrafish (Danio rerio)

Antibiotics are widely used around the world. Pollution of Sulfamethoxazole (SMX) in water poses a great threat to aquatic life. In this study, the toxic effects of SMX on the liver were assessed through RNA sequencing analysis and 16S rRNA sequencing analysis was conducted to determine the influence of SMX on gut microbiota of zebrafish (Danio rerio). Adult male zebrafish were exposed to 0, 5, 90 and 450 μg/L of environmentally relevant concentrations of SMX for 21 days respectively. The results showed that the liver had severe histopathological damages including pyknotic nuclei, cytoplasmic hyalinization and vacuolization and deformed hepatocytes with loose cell-to-cell contact. Transcriptomic analysis revealed that liver function was seriously affected by SMX exposure. Meanwhile, SMX exposure significantly inhibited the expression of genes associated with fatty acid synthesis, oxidation and transport. Besides, exfoliated and dissolved epithelial cells were observed in the gut after SMX treatment. Although there was no significant change on richness and species diversity of intestinal microbial community, the relative abundance of phylum and genus of SMX treatments were significantly different from that of control group. The present study implied that SMX may cause potential health risks to fish through inducing histopathological damages, genetic expression alterations, disorder of fatty acid metabolism and intestinal microbiota dysbiosis.

The effects of chronic cadmium exposure on Bufo gargarizans larvae: Histopathological impairment, gene expression alteration and fatty acid metabolism disorder in the liver

Cadmium (Cd) a highly toxic metal to human and wildlife health and it is hazardous to both terrestrial and aquatic life. In this study, we used RNA sequencing analysis to examine the effects of chronic cadmium exposure on liver lipid metabolism of Bufo gargarizans larvae. Tadpoles were exposed to cadmium concentrations at 0, 5, 10, 50, 100 and 200 μg L−1 from Gosner stage 26–42 of metamorphic climax. The results showed high dose cadmium (50, 100 and 200 μg L−1) caused obvious histological changes characterized by hepatocytes deformation, nuclear pyknosis, increasing melanomacrophage centers (MMCs) and aggregated lipid droplets. Moreover, transcriptome analysis showed that liver function was seriously affected by cadmium exposure. Furthermore, high dose cadmium significantly upregulated the mRNA expression of elongation of very-long-chain fatty acids 1 (ELOVL1), Mitochondrial trans-2-enoyl-CoA reductase (MECR), Trans-2, 3-enoyl-CoA reductase (TER) and Hydroxysteroid (17β) dehydrogenase type 12 (HSD17B12) which are related with fatty acid synthesis. Meanwhile, mRNA levels of genes related with fat acid oxidation such as acetyl-CoA acyltransferase 2 (ACAA2) and enoyl-coenzyme A (CoA) hydratase short chain 1 (ECHS1) were significantly upregulated while the expression of Acyl-coA thioesterase 1 (ACOT1), 3-hydroxyacyl-CoA dehydrogenase (HADH), Palmitoyl-protein thioesterase 1(PPT1) and Acetyl-CoA acyltransferase 1(ACAA1) was significantly downregulated by high dose cadmium exposure. Furthermore, the mRNA level of ATP-binding cassette subfamily B member 11 (ABCB11) related with bile secretion was significantly decreased exposed to high dose cadmium. Our results suggested cadmium can cause liver dysfunction by inducing histopathological damages, genetic expression alterations and fatty acid metabolism disorder.

Epigenetic Changes in Asthma: Role of DNA CpG Methylation.

For the past three decades, more than a thousand of genetic studies have been performed to find out the genetic variants responsible for the risk of asthma. Until now, all of the discovered single nucleotide polymorphisms have explained genetic effects less than initially expected. Thus, clarification of environmental factors has been brought up to overcome the ‘missing’ heritability. The most exciting solution is epigenesis because it intervenes at the junction between the genome and the environment. Epigenesis is an alteration of genetic expression without changes of DNA sequence caused by environmental factors such as nutrients, allergens, cigarette smoke, air pollutants, use of drugs and infectious agents during pre- and post-natal periods and even in adulthood. Three major forms of epigenesis are composed of DNA methylation, histone modifications, and specific microRNA. Recently, several studies have been published on epigenesis in asthma and allergy as a powerful tool for research of genetic heritability in asthma albeit epigenetic changes are at the starting point to obtain the data on specific phenotypes of asthma. In this presentation, we mainly review the potential role of DNA CpG methylation in the risk of asthma and its sub-phenotypes including nonsteroidal anti-inflammatory exacerbated respiratory diseases.

Epigenetics, diseases and therapy in ophthalmology

Heritable changes in gene expression are regarded as epigenetics, which do not involve coding sequence modifications. The study of ophthalmology epigenetics is a rapidly growing area in biomedical research. Epigenetic mechanisms principally include DNA methylation, histone modification, chromatin remodeling and non-coding RNA. Aberrant DNA methylation and histone modification are linked to a number of age-related disorders, such as cancer, autoimmune and others. In recent years, the modulations of epigenetic changes on the pathogenesis of eye disorders and their roles in therapeutic interventions are drawing more and more attention, and these studies deepen the understanding of relevant diseases. Since the epigenetic alterations are reversible, modifying epigenetic marks contributing to eye diseases provide a new approach to the development of disease prevention, diagnosis and therapies. Herein we discuss the roles of epigenetic changes in eye disease development, hoping that ophthalmologists and researchers pay attention to these researching cues in pathogenesis of eye disorders caused by genetic expression alterations in response to environmental changes, importantly, to the implication for relevant eye disease therapy and prevention. Key words: Epigenesis, genetic; Eye/genetic; Eye disorder/therapy; DNA methylation; Histones; MicroRNA

Updates in the neuroendocrinology of stress and its clinical management.

This review will provide updates on the neurobiology of stress, with specific focus on the transmitting mechanism of stress, the intricacies of integrating stress-related information, variability in response to stressors and clinical interventions. Neuropeptides have been implicated as a potential modulator for pathological stress via effects on neurogenesis, alterations in functional states of the cortico-limbic circuits and possible neuroprotection. Glucocorticoid receptors and mineralocorticoid receptors have been implicated in limbic modulation of stress and changes in the hypothalamic pituitary adrenal axis activity via corticosteroid signalling and feedback regulation. Chronic stress and genetic susceptibility have been found to promote intracellular mitochondrial and cellular DNA damage resulting in structural and functional alterations of neuroanatomy and neural circuitries. The interplay of stress and the neuroendocrine system appears to be influenced by alterations in genetic expression, resulting in neurochemical messenger and inflammatory cytokine alterations that impact neuroanatomy and neural circuitries to affect both central nervous system structure and function. These neurobiological contributions have been alluded to as possible contributors to stress-related psychopathologies. Clinical interventions with psychotropics, mind body therapies and behavioural therapies have been found to attenuate and reverse stress-related responses.

Abstract 12008: Nos1 Adapter Protein Nos1ap Overexpression Alters Qtc Intervals in Transgenic Mice

Background: Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from rare disease-causing mutations in ion channels, common genetic variations in the neuronal nitric oxide synthase (NOS1) regulator NOS1AP, have recently been associated with QT interval variations in a human whole-genome association study. In fact, NOS1AP SNPs have been linked to increases in QTc intervals and sudden cardiac death. We therefore speculate that myocardial NOS1AP overexpression may lead to a decrease of the QTc interval and an increased susceptibility to rhythm disorders. Methods and Results: We generated transgenic mice (TG) with a conditional myocardial NOS1AP overexpression and focused on electrical alterations. Conditional overexpression of NOS1AP resulted in a 147% ventricular increase in TG mice compared to WT littermates. NOS1AP was mainly located at the sarcolemma where it interacted with NOS1 and the L-type Ca2+- channel. HW/BW ratio, ventricular ANP expression, ventricular cross-sectional area and collagen deposition were not altered in NOS1AP mice under baseline conditions. However, NOS1AP overexpressing mice showed a clear decrease of QTc intervals (33 vs. 48 ms). They were more prone to bradycardia (resting heart rate 467 bpm vs. 666 bpm). Atrial programmed stimulation repeatedly caused atrial tachycardia. Ventricular programmed stimulation caused VT in some mice with NOS1AP overexpression. We also investigated the functional effect of the human rs16847548 (T/C). We found that this SNP decreased NOS1AP promoter activity in a viral NOS1AP luciferase assay, suggesting that this SNP downregulates NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to a significant shortening of the QTc interval with an increased susceptibility to atrial and ventricular rhythm disorders. SNP rs16847548 in NOS1AP resulted in downregulation of NOS1AP expression which provides an explanation for elongation of QTc intervals. In summary, not only a mutation in ion channels itself but also genetic alterations in expression of ion channel modifiers, such as NOS1AP, have an impact on QTc intervals.

A modified Glenn shunt reduces venous congestion during acute right ventricular failure due to pulmonary banding: a randomized experimental study

Right ventricular failure after left ventricular assist device implantation is a serious complication with high rates of mortality and morbidity. It has been demonstrated in experimental settings that volume exclusion of the right ventricle with a modified Glenn shunt can improve haemodynamics during ischaemic right ventricular failure. However, the concept of a modified Glenn shunt is dependent on a normal pulmonary vascular resistance, which can limit its use in some patients. The aim of this study was to explore the effects of volume exclusion with a modified Glenn shunt during right ventricular failure due to pulmonary banding, and to study the alterations in genetic expression in the right ventricle due to pressure and volume overload. Experimental right ventricular failure was induced in pigs (n = 11) through 2 h of pulmonary banding. The pigs were randomized to either treatment with a modified Glenn shunt and pulmonary banding (n = 6) or solely pulmonary banding (n = 5) as a control group. Haemodynamic measurements, blood samples and right ventricular biopsies for genetic analysis were sampled at baseline, at right ventricular failure (i.e. 2 h of pulmonary banding) and 1 h post-right ventricular failure in both groups. Right atrial pressure increased from 10 mmHg (9.0-12) to 18 mmHg (16-22) (P < 0.01) and the right ventricular pressure from 31 mmHg (26-35) to 57 mmHg (49-61) (P < 0.01) after pulmonary banding. Subsequent treatment with the modified Glenn shunt resulted in a decrease in right atrial pressure to 13 mmHg (11-14) (P = 0.03). In the control group, right atrial pressure was unchanged at 19 mmHg (16-20) (P = 0.18). At right heart failure, there was an up-regulation of genes associated with heart failure, inflammation, angiogenesis, negative regulation of cell death and proliferation. Volume exclusion with a modified Glenn shunt during right ventricular failure reduced venous congestion compared with the control group. The state of right heart failure was verified through genetic expressional changes.

Asthma and epigenetics

For the past two decades, a huge number of genetic studies have been conducted to identify the genetic variants responsible for asthma risk. Several types of genetic and genomic approaches, including linkage analysis, candidate gene single nucleotide polymorphism studies, and whole genome-wide association studies have been applied. However, the genetic impacts of these studies are minimal because asthma is a complex syndrome affected by interaction with many environmental factors mediated by epigenetics. Epigenetics is alteration of genetic expression without changes of DNA sequence. Three major forms of epigenetic is DNA methylation, histone modfications and specific microRNA expression that are known to have vast effects on gene expression. However, knowledge regarding the epigenetic effect on the development of asthma and its traits is limited up to date. Recently, new data on epigenetics have been brought up to explain the phenotypic alterations of asthma. In this review, we present general concept of epigenetics, environmental factors inducting epigenetic changes and the background mechanisms in epigenetics behind development asthma and epigenetic therapy. (Allergy Asthma Respir Dis 1(1):4-10, 2013)Allergy Asthma Respir Dis 1(1):4-10, 2013)

Upregulated ank expression in osteoarthritis can promote both chondrocyte MMP-13 expression and calcification via chondrocyte extracellular PP i excess

Objective: In idiopathic chondrocalcinosis and in osteoarthritis (OA), increased extracellular PP i (ecPP i) promotes calcification. In chromosome 5p-associated familial chondrocalcinotic degenerative arthropathy, certain mutations in the membrane protein ANK may chronically raise ecPP i via enhanced PP i channeling. Therefore, we assessed if dysregulated wild-type ANK expression could contribute to pathogenesis of idiopathic degenerative arthropathy through elevated ecPP i. Design: Using cells with genetic alterations in expression of ANK and the PP i-generating nucleotide pyrophosphatase phosphodiestrase (NPP) PC-1, we examined how increased ANK expression elevates ecPPI, testing for codependent effects with PC-1. We also evaluated the effects of ANK expression on chondrocyte growth, matrix synthesis, and MMP-13 expression and we immunohistochemically examined ANK expression in situ in human knee OA cartilages. Results: Using cells expressing defective ANK, as well as PC-1 knockout cells, we demonstrated that ANK required PC-1 (and vice versa) to raise ecPP i and that the major ecPP i regulator TGFβ required both ANK and PC-1 to elevate ecPP i. Upregulation of wild-type ANK by transfection in normal chondrocytes not only raised ecPP i 5-fold to ∼100 nM but also directly stimulated matrix calcification and inhibited collagen and sulfated proteoglycans synthesis. In addition, upregulated ANK induced chondrocyte MMP-13, an effect that also was stimulated within 2 h by treatment of chondrocytes with 100 nM PP i alone. Finally, ANK expression was upregulated in situ in human knee OA cartilages. Conclusion: Elevation of ecPP i by ANK critically requires the fraction of cellular PP i generated by PC-1. The upregulation of ANK expression in OA cartilage and the capacity of increased ANK expression to induce MMP-13 and to promote matrix loss suggest that increased ANK expression and ecPP i exert noxious effects in degenerative arthropathies beyond stimulation of calcification.

Stage-specific gene expression during hepatocarcinogenesis in the rat.

The alteration of genetic expression ubiquitously seen in both preneoplastic and neoplastic tissues has been investigated for many years in the hope that the critical molecular changes resulting in cancer can be elucidated. The alteration of the expression of specific genes has already been employed in diagnostic and even screening procedures for this disease. In the past many observations of such alterations have led to a variety of theories but not definitive generalizations. Studies of the alteration of genetic expression may now be viewed in the light of our understanding of the multistage nature of neoplastic development. This brief review describes a number of genes the expressions of which are altered during the stages of initiation and promotion, in contrast to the alteration of expression of genes during the stage of progression. The promotion stage is concerned primarily with the chronic interaction of promoting agents in the environment with the genetic apparatus of the cell, played out on the altered genetic background resulting from the stage of initiation. In contrast, the progression stage is characterized primarily by an evolving karyotypic instability resulting in continual genetic changes during this stage. On the basis of these distinctions it is possible to identify genes the altered expression of which is unique to the stage of progression. The identification of these genes and an understanding of mechanisms resulting in their altered expression will allow not only a better molecular characterization of the progression stage but also the quantitative analysis of neoplastic development in several model animal systems as well as eventually in the human.

The role of receptors in multistage carcinogenesis

The principal characteristic of neoplasia is its inherited alteration of genetic expression. The regulation of gene expression may be altered both by mutational events and by environmental mediators. During carcinogenesis the permanent alterations in genetic expression resulting from mutations occur primarily during the final stage of progression when biological malignancy becomes evident. During the preceding reversible stage of promotion, alteration and genetic expression are the result of the chronic stimulation of an altered (initiated) cell responding to the environmental mediator or promoting agent. A major mechanism of this effect occurs by receptors exhibiting specificity for the mediator and for their interaction with the genome. Withdrawal of the promoting agent prior to the genetic alterations characteristic of the stage of progression leads to a reversal of the effects of the promoting agent and the death by apoptosis of most cells in the stage of promotion. Carcinogenesis mediated by the chronic ligand (promoting agent)-receptor interaction increases the probability of the development of the stage of progression; thus alteration or prevention of the stage of promotion by removal of the promoting agent or inhibition of its action remains the best opportunity for cancer prevention. Application of the reversible promoting agent-receptor interaction to specific environmental circumstances where such plays a major role can lead to a more rational risk estimation of promoting agents for the human population.

Proteins of BrdU-Dependent Hamster Cell Lines as Characterized by Two-Dimensional Gel Electrophoresis

Cell lines which exhibit the BrdU-dependent phenotype (B4 and HAB) were studied with respect to BrdU-induced alterations in genetic expression by two-dimensional gel electrophoresis. A comparison of the proteins from the HAB cells, in which the DNA is 100% substituted by BrdU, to those of the unsubstituted parent line (3460) showed 55 protein alterations; the synthesis of 15 increased while that of the other 40 decreased. When 3460 cells were grown in BrdU such that their DNA was greater than 50% substituted, 27 protein changes could be detected; of these, the synthesis of 10 increased while that of 17 decreased. A comparison of all these changes in the various cell lines showed six which were common to the BrdU-substituted cell lines. The proteins from another Syrian hamster cell line, BHK-21 (C-13) and those of HAB cells grown in thymidine or BrdC were also examined on two-dimensional gels. Although BrdU has a dramatic effect on many cellular functions, relatively few changes in the pattern of protein synthesis could be detected in these cell lines, perhaps reflecting the specialized action of this analogue on particular cellular functions.