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At least 631 records · Page 35Linked to original sources
PubMed2006

Epigenetic heterochromatin markers distinguish terminally differentiated leukocytes from incompletely differentiated leukemia cells in human blood.

OBJECTIVE: During terminal cell differentiation, nuclear chromatin becomes condensed and the repertoire of epigentic heterochromatin proteins responsible for chromatin condensation is dramatically changed. In order to identify the chromatin regulatory factors associated with incomplete cell differentiation and impaired chromatin condensation in hematological malignancies, we examined expression levels of major heterochromatin proteins in normal blood cells and cells derived from a number of chronic and acute myeloid leukemia patients exhibiting different degrees of differentiation. METHODS: We used immunoblotting and immunofluorescence to examine the levels and localization of epigenetic heterochromatin factors in isolated cell nuclei and fractionated peripheral blood cells. RESULTS: While the major epigenetic heterochromatin factor, histone H3 methylated at lysine 9, is present in all cell types, its main counterparts, nonhistone proteins, heterochromatin proteins 1 (HP1) alpha, beta, and gamma, are dramatically reduced in peripheral blood leukocytes of normal donors and chronic myeloid leukemia patients, but are substantially increased in the blood of accelerated phase and blast crisis patients. In the terminally differentiated cells, nuclear chromatin accumulates a nucleocytoplasmic serpin, monocyte and neutrophil elastase inhibitor (MNEI). HP1 and MNEI levels inversely correlate in a number of normal and leukemia myeloid cells and show strikingly opposite coordinated changes during differentiation of U937 cell line induced by retinoic acid. CONCLUSIONS: Our results suggest that repression of HP1 and accumulation of MNEI are linked to terminal cell differentiation and that their levels may be monitored in blood cell populations to detect transitions in cell differentiation associated with leukemia progression and treatment.

Antineoplastic Agents↗
PubMed2004

Genetic and epigenetic modulation of telomerase activity in development and disease.

Telomerase activity is one of the most important factors that have been linked to multiple developmental processes, including cell proliferation, differentiation, aging and senescence. Dysregulation of telomerase has often been found in developmental abnormalities, such as cancer, loss of function in the hematopoietic system, and low success rate of somatic cloning. A comprehensive network of transcription factors has been shown to be involved in the genetic control of telomerase expression and activity. Epigenetic mechanisms have recently been shown to provide an additional level of regulation, and may be responsible for the diverse expression status of telomerase that is manifested in a tissue and cell-type-dependent manner. This article summarizes the recent developments in the field of telomerase research with a focus on the coregulation of the telomerase gene by both genetic and epigenetic pathways. Developmental consequences of aberrant telomerase activity will also be summarized and discussed.

Aging↗
PubMed2006

Stochastic epigenetic silencing of retrotransposons: does stability come with age?

It has been hypothesized that phenotypic variation in mammals could in part be due to incomplete and variable silencing of retrotransposons in somatic cells. This theory is based on the fact that some recent endogenous retroviral (ERV) insertions in the mouse exert variable effects on genes in isogenic animals, depending on the variable state of ERV methylation. In this article, we review the evidence for this and related phenomena and suggest that such stochastic epigenetic silencing is restricted to very recent insertions. We also present a model to explain the acquisition of a more stable epigenetic state for transposable element insertions through time.

Animals↗
PubMed2006

Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo.

PURPOSE: Although modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem. Among various complications, radiation also poses a threat to the progeny of exposed parents. It causes transgenerational genome instability that is linked to transgenerational carcinogenesis. Although the occurrence of transgenerational genome instability, which manifests as elevated delayed and nontargeted mutation, has been well documented, the mechanisms by which it arises remain obscure. We hypothesized that epigenetic alterations may play a pivotal role in the molecular etiology of transgenerational genome instability. METHODS AND MATERIALS: We studied the levels of cytosine DNA methylation in somatic tissues of unexposed offspring upon maternal, paternal, or combined parental exposure. RESULTS: We observed a significant loss of global cytosine DNA methylation in the thymus tissue of the offspring upon combined parental exposure. The loss of DNA methylation was paralleled by a significant decrease in the levels of maintenance (DNMT1) and de novo methyltransferases DNMT3a and 3b and methyl-CpG-binding protein MeCP2. Along with profound changes in DNA methylation, we noted a significant accumulation of DNA strand breaks in thymus, which is a radiation carcinogenesis target organ. CONCLUSIONS: The observed changes were indicative of a profound epigenetic dysregulation in the offspring, which in turn could lead to genome destabilization and possibly could serve as precursor for transgenerational carcinogenesis. Future studies are clearly needed to address the cellular and carcinogenic repercussions of those changes.

Animals↗
PubMed2006

Epigenetic regulation of MHC-II and CIITA genes.

This review describes recent advances in understanding how epigenetic events control MHC-class-II-family (MHC-II) gene expression. To address this issue, two phases of gene transcription have to be considered. First, the control of MHC-II by chromatin-modifying events such as histone acetylation, methylation, deacetylation, ubiquitination and the interplay between these different epigenetic events will be examined. The interactions of chromatin-modifying enzymes with class II transactivator (CIITA) and relevant DNA-binding proteins for activating and silencing MHC-II gene transcription will be reviewed. Second, the transcriptional control of the promoter of CIITA, the master regulator of MHC-II, by DNA methylation and chromatin modification will be discussed, and the novel role of noncoding RNA will be explored. Finally, the relevance of these findings to infection, transplantation and cancer will be reviewed.

Animals↗
PubMed2004

Genetics, epigenetics, and the environment: switching, buffering, releasing.

Increasing evidence suggests that the interactions between genes and environment might play a critical role in the pathogenesis of complex diseases, such as asthma, that exhibit a heritable component but do not follow Mendel's laws. Gene-environment interactions are extremely complex and not linear, such that the same genetic variants might be associated with opposite phenotypes in different environments. This is particularly evident for innate immunity genes, which operate at the interface between the immune system and the pathogen world. This article examines gene-environment interactions by using CD14 as a model and argues that the conflicting results of epidemiologic studies on CD14*C-159T result from differences in environmental conditions essential to modulate CD14 gene expression. Furthermore, on the basis of how rapidly environmental changes have affected the incidence of immune diseases, I argue that a full understanding of gene-environment interactions requires that epigenetic as well as classical genetic mechanisms be taken into account. Recent data about the effect of diet on gene methylation and the release of hidden genetic variation by impairment of heat shock protein 90-mediated buffering systems offer eloquent examples of how epigenetic mechanisms might affect gene-environment interactions.

DNA Methylation↗
PubMed2024

Androgen Effects on Alcohol-induced Liver Fibrosis Are Controlled by a Notch-dependent Epigenetic Switch.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex is an important variable; however, the mechanism behind sex differences is not yet established. METHODS: Kdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2 × 1011 genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10 mg/kg of avagacestat for 4 weeks. RESULTS: We found that Kdm5b/Kdm5c knockout promoted alcohol-induced liver disease, whereas gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the androgen receptor role in liver fibrosis. Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss. CONCLUSIONS: Male sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.

Animals↗
PubMed2026

Molecular mechanisms of plant thermal response: from signal transduction and epigenetic regulation to signaling integration.

Global warming intensification elevates heat stress to one of the major threats to crop productivity. This review synthesizes recent advances in understanding the mechanisms governing plant responses to both moderate and acute heat stress, with a focus on the integration of epigenetic regulation and signaling networks that underpin thermal adaptation. This review highlights how transcription factors PHYTOCHROME-INTERACTING FACTOR 4 (PIF4, during thermomorphogenesis) and HEAT SHOCK FACTOR A1s (HSFA1s, in heat shock responses) orchestrate plant adaptive growth through crosstalk among light, circadian, and hormone signaling pathways. Importantly, epigenetic mechanisms, including histone variant H2A.Z dynamics and histone modification reprogramming, function as central regulators of thermal plasticity. Key among these processes are HSFA2-mediated chromatin remodeling and small interfering RNA (siRNA)-dependent control of transgenerational thermomemory. Despite this progress, fundamental questions persist regarding temperature sensing, HSFA1s activation dynamics, and stress signal integration. Multi-omics and synthetic biology approaches are proposed to be pivotal in deciphering conserved principles of plant thermal resilience, ultimately providing a theoretical foundation and molecular breeding strategies for climate-smart crops.

Epigenesis, Genetic↗
PubMed2004

Identification of genes up-regulated by histone deacetylase inhibition with cDNA microarray and exploration of epigenetic alterations on hepatoma cells.

BACKGROUND/AIMS: Epigenetics is the key factor in the regulation of gene expression. We conducted cDNA microarray analysis to screen for genes induced by histone deacetylase (HDAC) inhibition and examined epigenetic alterations. METHODS: Microarray analysis was performed in six hepatoma cell lines and primary hepatocytes treated with trichostatin A (TSA). mRNA expression of several genes was examined by reverse transcription-polymerase chain reaction in TSA-treated cells and hepatoma samples. Acetylated histones and methylation status in 5'CpG islands was assessed by chromatin immunoprecipitation (ChIP) assay and bisulfite genomic sequencing, respectively. RESULTS: Fifty-seven genes showed greater than 2-fold change after TSA treatment in multiple cell lines. Among them, four genes including p21(WAF1) exhibited substantial induction (greater than 5-fold changes). Decreased mRNA levels of these genes in hepatoma tissues were observed in more than half of patients. ChIP assay, in general, demonstrated a good correlation between mRNA expression and histone acetylation, but only a limited correlation with the methylated DNA in the promoter region. CONCLUSIONS: We identified 57 up-regulated genes by TSA treatment in hepatoma cells and some of them appeared to be cancer-related genes in hepatomas. The alterations in acetylated histones are likely closely associated with gene expression.

Acetylation↗
PubMed2026

Maternal high-fat diet modulates lupus nephritis through fetal Wnt-steroid hormone and epigenetic reprogramming in MRL/lpr mouse offspring.

We previously investigated whether maternal high-fat diet (HFD) exposure alters lupus nephritis (LN) progression in MRL/lpr offspring. Contrary to expectation, maternally HFD-exposed offspring showed delayed and attenuated nephritic progression compared with control diet offspring. The maternal HFD developmental impact on LN remains unclear. Here, integrated amniotic fluid metabolomics and fetal liver transcriptomics revealed that maternal HFD reshaped the intrauterine molecular environment, particularly involving steroid hormone biosynthesis and Wnt/β-catenin-associated regulatory networks. Methylome profiling further demonstrated broad CpG hypomethylation, immune-related differentially methylated region enrichment, and an inverse association between global CpG methylation and oxidative genomic DNA damage. Among candidate regulatory nodes, Axin2, a canonical Wnt/β-catenin target and feedback regulator, emerged as a potential link between fetal nutritional exposure, epigenetic remodeling, and persistent pathway modulation. Although whole-locus and gene body methylation of Axin2 were not markedly altered, promoter-region methylation showed an increasing tendency under maternal HFD exposure. In adult offspring, maternal HFD was associated with reduced Axin2 protein expression, decreased Wnt-responsive transcripts, increased peripheral corticosterone levels, and attenuation of LN progression. The inverse association between Axin2 expression and corticosterone further suggested coupling between suppressed Wnt pathway output and steroid hormone remodeling. Together, these findings support a developmental model in which maternal HFD reshapes the fetal intrauterine environment and establishes a persistent Wnt-steroid hormone-epigenetic regulatory axis that unexpectedly attenuates LN progression in genetically susceptible offspring.

Axin2↗
PubMed2006

Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia.

Genetic and epigenetic factors can potentially alter susceptibility to psychiatric disorders such as schizophrenia. In order to explore the effect of epigenetics on the pathogenesis of schizophrenia, we examined the global methylation level of leukocyte DNA from 210 patients with schizophrenia (124 males and 86 females) and 237 healthy subjects (108 males and 129 females). Methylated deoxycytidine (mC) content in peripheral leukocyte DNA was measured by high performance liquid chromatography (HPLC). We confirmed in the healthy subjects our previous finding that there are sex-dependent differences in mC content (males>females; beta=0.319, p<0.001), in addition to the effect of age (beta=-0.141, p=0.022). We therefore used multiple regression to analyze the data from all subjects by sex, with age as a co-variant. In males, a tendency was observed toward lower mC content in patients than in controls (beta=-0.115, p=0.075), with a significant effect of age (beta=-0.212, p<0.001). This difference was more prominent in younger individuals. In females, no effect of age or disease status on mC content was observed. These results established that there is significant sex-dependent difference in the mC content of human peripheral leukocyte DNA, and raise the possibility that alterations in DNA methylation state are present in patients with schizophrenia.

Adolescent↗
PubMed2006

Nutritional modulation of ageing: genomic and epigenetic approaches.

Dietary factors have a profound effect on many aspects of health including ageing and do so, at least partly, through interactions with the genome which result in altered gene expression. The application of high throughput genomics technologies in nutritional research (nutrigenomics) offers a new approach to understanding the molecular mechanisms by which nutrition affects ageing. To date, transcriptional profiling techniques have been applied in studies of the mode of action of energy (caloric) restriction. Two further areas which appear to be particularly promising are (i) nutritional modulation of DNA damage and repair and (ii) nutritional modulation of epigenetic markings. Epigenetic-mediated changes in gene expression in response to dietary and other lifestyle exposures appear to be a major molecular mechanism linking environmental factors with the genome with consequences for cell function and health throughout the life course.

Aged↗
PubMed2006

The genetics and epigenetics of altered proliferative homeostasis in ageing and cancer.

Ageing mammals are subject to an amazing array of aberrations in proliferative homeostasis. These are of two basic types: the post-maturational failure to adequately replace effete somatic cells (atrophies) and excessive proliferations of somatic cells (hyperplasias). To a surprising degree, these occur side by side within the same tissues and are features of numerous mammalian geriatric disorders. Atrophy is the likely usual initial event, the proliferative response perhaps developing as a secondary, compensatory, initially adaptive reaction. We have little understanding of why this putative compensatory reaction so often fails to be appropriately regulated in ageing mammals, leading to such pathologies as chronic inflammation, fibrosis, metaplasia and neoplasia. Advances in formal genetic analysis, mutagenesis, stem cell biology and epigenetics are likely to provide major new understanding. Stochastic epigenetic shifts in gene expression are of growing interest, particularly in explaining intra-specific variations on rates and patterns of ageing. Nature may well have evolved such random fluctuations in gene expression as a type of group-selectionist adaptive strategy to cope with diverse stochastic environmental challenges. Alternatively, such background "noise" in transcription and translation may simply reflect a type of informational entropy.

Aging↗
PubMed2005

Autoimmune disorders result from loss of epigenetic control following chromosome damage.

Multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis share common features in typical cases such as: adult onset, central nervous system problems, female predominance, episodes triggered by a variety of stresses, and an autoimmune reaction. At times, the different disorders are found in the same patient or close relatives. These disorders are quite complex but they may share a common mechanism that results in different, tissue-specific consequences based on the cell types in which the mechanism occurs. Here, it is hypothesized that DNA damage can lead to loss of epigenetic control, particularly when the damaged chromatin is distributed unevenly to daughter cells. Expression of genes and pseudogenes that have lost their epigenetic restraints can lead to autoimmune disorders. Loss of control of genes on the X chromosome and loss of control of polyamine expression are discussed as examples of this mechanism.

Apoptosis↗
PubMed2005

Does dysregulation of key epigenetic and biochemical pathways occur in postulated vasoactive neuropeptide autoimmune disorders?

Autoimmune dysfunction of certain vasoactive neuropeptides (VNs) has been postulated as a contributing cause of sudden infant death syndrome (SIDS), chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and other fatigue-related disorders. This family of VNs includes pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP). The postulated mechanism is compromise of adenylate cyclase activation, a vital and unique step in cyclic AMP production from ATP, through autoimmune dysfunction of VNs, their receptors or their genes possibly involving cytosine-phosphate-guanine (CpG) fragments. CpG fragments are immunomodulatory dinucleotides serving as 'friend or foe' recognition systems to differentiate bacterial and viral (hypomethylated CpG) from mammalian (methylated CpG) DNA. However hypomethylation disorders affecting these fragments in mammals may convert them to dysfunctional states by promoting autoimmune inflammatory reactions. Epigenetic mechanisms acting on gene promoter regions may contribute to the development of VN autoimmune fatigue-related disorders through CpG fragments located in vital segments of VN/receptor genes by causing signalling defects with profound implications for VN function. Neurotransmitter dysfunction particularly glutamatergic transmission could also result with disruption of neuronal cellular biochemical functions such as ammonia regulation. Endosomal acidity and mitochondrial membrane potential modifiers such as chloroquine, together with immunoregulatory therapies, may have therapeutic implications in protecting against these apparent autoimmune disorders. This paper examines specific epigenetic and biochemical mechanisms possibly mediated by VN or receptor genes resulting in postulated VN autoimmune fatigue-related disorders. These mechanisms may have implications for treatment and prevention options for VN autoimmune disorders. VN autoimmune processes have implications for military medicine where radiological, chemical and biological agents may play an important role in pathogenesis.

Autoimmune Diseases↗
PubMed2006

When normal is not: the dilemma of interpreting laboratory averages of bioactive molecules subject to heterogeneous regulatory feedback and epigenetic mosaicism.

Complex regulatory systems control the levels of many bioactive molecules in the serum. These systems involve the integration of feedback responses from numerous tissues. End-organs and tissues can manifest epigenetic mosaicism, particularly with aging or disease states. We propose that an isolated lab value may reflect a blended average of inhomogeneous feedback responses from target tissues in various states of dysfunction. Reliance on such data may underestimate the state of systemic dysfunction. Yet in clinical practice, normal serum levels of a given molecule and its associated regulatory machinery are often assumed to reflect normal body homeostasis and tissue function. Organism-wide integration of abnormally high and low levels of bioactivity of a molecule in different tissues may yield apparently normal serum values of the bioactive molecule and known components of its regulatory system. We specifically discuss thyroid hormone regulation and function as a case example. Epigenetic reprogramming of either regulatory loops or tissue responses represents another way in which normal serum levels of the molecule may obscure target-organ dysfunction. The proposed idea has broad implications for disease pathogenesis, diagnosis, and therapies. A model where individual tissues employ illegitimate signaling to subvert the concerns of the organism as a whole is also proposed.

Animals↗
PubMed2006

Why are immigrants at increased risk for psychosis? Vitamin D insufficiency, epigenetic mechanisms, or both?

European researchers have observed that schizophrenia is 3 times more frequent in immigrants than in native-born subjects. This increased risk is even higher in dark-skinned immigrants, and the second generation is more affected than the first one. Immigrant status is an important environmental risk factor not only for schizophrenia but also for other psychoses. The explanations proposed to date have been mainly related to epidemiological biases and psychological reasons, such as racism or social defeat, but no biological hypotheses have been tested so far. This article proposes two biological hypotheses related to changes in sun exposure, changes in diet, and stress associated with immigration, which would explain the increased risk for psychosis associated with immigrant status. (1) Vitamin D insufficiency has been proposed as a risk factor for schizophrenia. The main source of vitamin D is through photosynthesis by sun exposure, and dark skins need more sun exposure to maintain adequate blood levels. Vitamin D insufficiency in adulthood could explain why dark-skinned immigrants develop psychosis when moving to high latitude countries, and its insufficiency during pregnancy could explain why the observed risk is higher in the second generation. (2) The second hypothesis is that of epigenetics, with psychosis resulting from modifications in gene expression caused by changes in diet and/or stress related to immigration. The role of homocysteine and the vitamin B-complex, especially folic acid, in these changes in DNA transcription would vary according to the polymorphism of the methylenetetrahydrofolate reductase gene. The vitamin D insufficiency and epigenetics hypotheses are consistent with yet unexplained findings well known in the epidemiology of schizophrenia, such as the increased risk in the urban environment, the excess of winter births, the excess of schizophrenia births after maternal famine, and the shorter interbirth period before a schizophrenia birth. In order to test these hypotheses, epidemiological studies of psychosis and immigration should include objective measures of skin color, which is predicted to be a more important risk factor than ethnicity. They should measure vitamin D, homocysteine and vitamin B-complex status and assess the polymorphisms of the vitamin D receptors and the methylenetetrahydrofolate reductase gene. If confirmed, these hypotheses would lead to effective and inexpensive preventive measures which would markedly decrease the rates of psychosis and schizophrenia, as well as the burden and stigma of these diseases, and greatly improve the mental health of immigrants.

Emigration and Immigration↗
PubMed2026

Low-Grade Myofibroblastic Sarcoma Represents an Epigenetically Distinct Myofibroblastic Tumor With USP6 Upregulation and Stable Genome.

Low-grade myofibroblastic sarcoma (LGMS) is a rare, indolent mesenchymal neoplasm exhibiting myofibroblastic differentiation, with a propensity for local recurrence. The molecular basis of LGMS and its precise relationship with other histological mimics have remained largely undefined. To address this gap, we conducted the first comprehensive multiomics analysis of 6 LGMS cases, integrating whole-exome sequencing, RNA sequencing, and Illumina Methylation EPICv2 array profiling with comparative analysis against public sarcoma methylation cohorts and related fibroblastic tumors. Clinically, patients (median age 35.5 years) presented with small tumors (median size 1.45 cm), predominantly located in the head and neck, displaying classic histological features of diffusely infiltrative spindle cell fascicles with patchy mononuclear inflammation. Two of the 5 patients with follow-up developed local recurrence, and none metastasized (median follow-up duration 92.5 months). Genomically, all LGMS exhibited a low tumor mutational burden (median 2.31 mut/Mb) and a minimal fraction of genome altered, with TP53 and TSC2 deletions and NTRK1 and ERBB3 amplifications found in a subset of cases. No pathogenic fusions were detected. Transcriptomic profiling revealed a distinct signature featuring prominent USP6 overexpression and upregulation of inflammatory and immune-related genes, including CD274 (PD-L1), and enrichment of inflammatory and interferon-gamma response signatures. Epigenetically, LGMS formed a unique methylation cluster closest to inflammatory myofibroblastic tumor, with numerous differentially methylated regions and higher immune infiltration, particularly monocytes, compared with other fibroblastic tumors. These findings establish LGMS as a genomically stable, epigenetically distinct myofibroblastic sarcoma driven by USP6 overexpression and an inflammation-enriched transcriptome. They support its recognition as a standalone entity, facilitate integration into methylation-based sarcoma classifiers for improved diagnostic precision, and nominate USP6-associated pathways and immune checkpoint blockade as promising therapeutic strategies for recurrent or unresectable disease.

Humans↗