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At least 19 recordsLinked to original sources
PubMed2002

From epigenesis to epigenetics: the case of C. H. Waddington.

One continuous thread in this volume is the name of Conrad H. Waddington (1905-1975), the developmental biologist known as the inventor of the term epigenetics. After some biographical notes on his life, this article explores the meaning of the Waddingtonian equation and the context wherein it was developed. This equation holds that epigenesis + genetics = epigenetics, and refers in retrospect to the debate on epigenesis versus preformationism in neoclassical embryology. Whereas Waddington actualized this debate by linking epigenesis to developmental biology and preformation to genetics, thereby stressing the importance of genetic action in causal embryology, today's epigenetics more and more offers the possibility to enfeeble biological thinking in terms of genes only, as it expands the gene-centric view in biology by introducing a flexible and pragmatically oriented hierarchy of crucial genomic contexts that go beyond the organism.

Animals↗
PubMed2003

Epigenetics and bipolar disorder: new opportunities and challenges.

Despite significant effort, understanding of the molecular causes and mechanisms of bipolar disorder (BD) remains a major challenge. Numerous molecular genetic linkage and association studies have been conducted over the last two decades; however, the data are quite inconsistent or even controversial. This article develops an argument that molecular studies of BD would benefit significantly from adding an epigenetic (epiG) perspective. EpiG factors refer to modifications of DNA and chromatin that "orchestrate" the activity of the genome, including regulation of gene expression. EpiG mechanisms are consistent with various non-Mendelian features of BD such as the relatively high degree of discordance in monozygotic (MZ) twins, the critical age group for susceptibility to the disease, clinical differences in males and females, and fluctuation of the disease course, including interchanges of manic and depressive phases, among others. Apart from the phenomenological consistency, molecular epiG peculiarities may shed new light on the understanding of controversial molecular genetic findings. The relevance of epigenetics for the molecular studies of BD is demonstrated using the examples of genetic studies of BD on chromosome 11p and the X chromosome. A spectrum of epiG mechanisms such as genomic imprinting, tissue-specific effects, paramutagenesis, and epiG polymorphism, as well as epiG regulation of X chromosome inactivation, is introduced. All this serves the goal of demonstrating that epiG factors cannot be ignored anymore in complex phenotypes such as BD, and systematic large-scale epiG studies of BD have to be initiated.

Bipolar Disorder↗
PubMed2005

DNA methylation 40 years later: Its role in human health and disease.

A long path, initiated more than 40 years ago, has led to a deeper understanding of the complexity of gene regulation in eukaryotic genomes. In addition to genetic mechanisms, the imbalance in the epigenetic control of gene expression may profoundly alter the finely tuned machinery leading to gene regulation. Here, we review the impact of the studies on DNA methylation, the "primadonna" in the epigenetic scenario, on the understanding of basic phenomena, such as X inactivation and genomic imprinting. The effect of deregulation of DNA methylation on human health, will be also discussed. Finally, an attempt to predict future directions of this rapidly evolving field has been proposed, with the certainty that, fortunately, science is always better than predictions.

DNA Methylation↗
PubMed2005

Methylation of DNA--one of the major epigenetic markers.

Regulation of gene expression is a complex process. It includes a great number of steps from control of mRNA synthesis to posttranslational modification of proteins. Epigenetic events play essential roles in regulation of transcription. In this review, we concentrate on methylation of DNA as one of the important epigenetic marks. It is well known that DNA methylation is associated with closed chromatin state and, therefore, repressed, inactive genes. Here we describe major processes that depend on DNA methylation: imprinting, X-inactivation, and oncogenesis. Also we describe a number of known methyl-DNA-binding proteins and links between methylation of DNA and higher-order chromatin structure.

Animals↗
PubMed2005

Tissue-specific reactivation of gene expression at an imprinted locus.

Genomic imprinting is the phenomenon where the expression pattern of an allele at a locus differs depending on the allele's parent of origin. In most cases, one of the two alleles is transcriptionally silent. Recent empirical work has shown some genes to be imprinted in a tissue-specific manner, where the silenced allele becomes reactivated in particular cell lineages during development. Here I describe an evolutionary model of tissue-specific transcriptional reactivation. The model describes the relationships among various inclusive fitness functions and phenotypic effects necessary for natural selection to favor the epigenetic reprogramming required for this sort of reactivation, and makes predictions regarding the nature and magnitude of phenotypic and fitness consequences of mutations in particular somatic tissues. In particular, if an imprinted gene is reactivated in one of two tissues that interact in producing a particular phenotype, expression of the gene in those two tissues is expected to have opposite phenotypic effects. The model predicts that in some cases, mutations affecting the silenced allele at an imprinted locus may be phenotypically more severe than those affecting the expressed allele. These predictions are contrasted with those of an alternative explanation for reactivation: protection against deleterious recessive somatic mutations. The inclusive-fitness model of reactivation indicates that the intragenomic conflicts present in the parental germ lines and developing embryo persist though adult life, and can have complex effects on phenotypes and patterns of gene expression in somatic tissues.

Alleles↗
PubMed2022

Enhancer and super-enhancer landscape in polycystic kidney disease.

Widespread aberrant gene expression is a pathological hallmark of polycystic kidney disease (PKD). Numerous pathogenic signaling cascades, including c-Myc, Fos, and Jun, are transactivated. However, the underlying epigenetic regulators are poorly defined. Here we show that H3K27ac, an acetylated modification of DNA packing protein histone H3 that marks active enhancers, is elevated in mouse and human samples of autosomal dominant PKD. Using comparative H3K27ac ChIP-Seq analysis, we mapped over 16000 active intronic and intergenic enhancer elements in Pkd1-mutant mouse kidneys. We found that the cystic kidney epigenetic landscape resembles that of a developing kidney, and over 90% of upregulated genes in Pkd1-mutant kidneys are co-housed with activated enhancers in the same topologically associated domains. Furthermore, we identified an evolutionarily conserved enhancer cluster downstream of the c-Myc gene and super-enhancers flanking both Jun and Fos loci in mouse and human models of autosomal dominant PKD. Deleting these regulatory elements reduced c-Myc, Jun, or Fos abundance and suppressed proliferation and 3D cyst growth of Pkd1-mutant cells. Finally, inhibiting glycolysis and glutaminolysis or activating Ppara in Pkd1-mutant cells lowerd global H3K27ac levels and its abundance on c-Myc enhancers. Thus, our work suggests that epigenetic rewiring mediates the transcriptomic dysregulation in PKD, and the regulatory elements can be targeted to slow cyst growth.

Animals↗
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↗
PubMed2006

CTCF-dependent chromatin insulator is linked to epigenetic remodeling.

Chromatin insulators are boundary elements between distinctly regulated, neighboring chromosomal domains, and they function by blocking the effects of nearby enhancers in a position-dependent manner. Here, we show that the SNF2-like chromodomain helicase protein CHD8 interacts with the insulator binding protein CTCF. Chromatin immunoprecipitation analysis revealed that CHD8 was present at known CTCF target sites, such as the differentially methylated region (DMR) of H19, the locus control region of beta-globin, and the promoter region of BRCA1 and c-myc genes. RNA interference-mediated knockdown of CHD8 significantly abolished the H19 DMR insulator activity that depends highly on CTCF, leading to reactivation of imprinted IGF2 from chromosome of maternal origin. Further, the lack of CHD8 affected CpG methylation and histone acetylation around the CTCF binding sites, adjacent to heterochromatin, of BRCA1 and c-myc genes. These findings provide insight into the role of CTCF-CHD8 complex in insulation and epigenetic regulation at active insulator sites.

Animals↗
PubMed2003

Mechanisms of insulator function in gene regulation and genomic imprinting.

Correct temporal and spatial patterns of gene expression are required to establish unique cell types. Several levels of genome organization are involved in achieving this intricate regulatory feat. Insulators are elements that modulate interactions between other cis-acting sequences and separate chromatin domains with distinct condensation states. Thus, they are proposed to play an important role in the partitioning of the genome into discrete realms of expression. This review focuses on the roles that insulators have in vivo and reviews models of insulator mechanisms in the light of current understanding of gene regulation.

Animals↗
PubMed2004

Reprogramming of epigenetic inheritance by somatic cell nuclear transfer.

Somatic cloning by nuclear transfer returns a differentiated cell to a totipotent stage, a process termed nuclear reprogramming. During this de-differentiation process, genes inactivated during tissue differentiation are re-activated in a temporal and spatial special manner. It is believed that tissue differentiation occurs through epigenetic mechanisms, genetic inheritance that does not involve changes in DNA sequences. Developmental abnormalities and a high mortality rate in cloned offspring have frequently been observed and probably result from incomplete nuclear reprogramming. In this review, the reprogramming of two epigenetic mechanisms, imprinting and X chromosome inactivation, as well as recent attempts to modify pre-existing epigenetic marks in donor cells to improve nuclear transfer efficacy, are discussed.

Animals↗
PubMed2006

Transgeneration memory of stress in plants.

Owing to their sessile nature, plants are constantly exposed to a multitude of environmental stresses to which they react with a battery of responses. The result is plant tolerance to conditions such as excessive or inadequate light, water, salt and temperature, and resistance to pathogens. Not only is plant physiology known to change under abiotic or biotic stress, but changes in the genome have also been identified. However, it was not determined whether plants from successive generations of the original, stressed plants inherited the capacity for genomic change. Here we show that in Arabidopsis thaliana plants treated with short-wavelength radiation (ultraviolet-C) or flagellin (an elicitor of plant defences), somatic homologous recombination of a transgenic reporter is increased in the treated population and these increased levels of homologous recombination persist in the subsequent, untreated generations. The epigenetic trait of enhanced homologous recombination could be transmitted through both the maternal and the paternal crossing partner, and proved to be dominant. The increase of the hyper-recombination state in generations subsequent to the treated generation was independent of the presence of the transgenic allele (the recombination substrate under consideration) in the treated plant. We conclude that environmental factors lead to increased genomic flexibility even in successive, untreated generations, and may increase the potential for adaptation.

Acclimatization↗
PubMed2004

Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes.

Imprinted genes are clustered in domains, and their allelic repression is mediated by imprinting control regions. These imprinting control regions are marked by DNA methylation, which is essential to maintain imprinting in the embryo. To explore how imprinting is regulated in placenta, we studied the Kcnq1 domain on mouse distal chromosome 7. This large domain is controlled by an intronic imprinting control region and comprises multiple genes that are imprinted in placenta, without the involvement of promoter DNA methylation. We found that the paternal repression along the domain involves acquisition of trimethylation at Lys27 and dimethylation at Lys9 of histone H3. Eed-Ezh2 Polycomb complexes are recruited to the paternal chromosome and potentially regulate its repressive histone methylation. Studies on embryonic stem cells and early embryos support our proposal that chromatin repression is established early in development and is maintained in the placenta. In the embryo, however, imprinting is stably maintained only at genes that have promoter DNA methylation. These data underscore the importance of histone methylation in placental imprinting and identify mechanistic similarities with X-chromosome inactivation in extraembryonic tissues, suggesting that the two epigenetic mechanisms are evolutionarily linked.

Animals↗
PubMed2006

Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR.

Coreceptor expression is tightly regulated during thymocyte development. Deletion of specific Cd8 enhancers leads to variegated expression of CD8alphabeta heterodimers in double-positive thymocytes. Here we show CD8 variegation is correlated with an epigenetic 'off' state, linking Cd8 enhancer function with chromatin remodeling of the adjacent genes Cd8a and Cd8b1 (Cd8). The zinc finger protein MAZR bound the Cd8 enhancer and interacted with the nuclear receptor corepressor N-CoR complex in double-negative thymocytes. MAZR was downregulated in double-positive and CD8 single-positive thymocytes. 'Enforced' expression of MAZR led to impaired Cd8 activation and variegated CD8 expression. Our results demonstrate epigenetic control of the Cd8 loci and identify MAZR as an important regulator of Cd8 expression.

Animals↗
PubMed2006

Insulators: exploiting transcriptional and epigenetic mechanisms.

Insulators are DNA sequence elements that prevent inappropriate interactions between adjacent chromatin domains. One type of insulator establishes domains that separate enhancers and promoters to block their interaction, whereas a second type creates a barrier against the spread of heterochromatin. Recent studies have provided important advances in our understanding of the modes of action of both types of insulator. These new insights also suggest that the mechanisms of action of both enhancer blockers and barriers might not be unique to these types of element, but instead are adaptations of other gene-regulatory mechanisms.

Animals↗
PubMed2026

HDAC inhibition via suberoylanilide hydroxamic acid ameliorates doxorubicin-induced cardiotoxicity.

Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy, and effective preventive strategies are lacking. Topoisomerase IIb has been implicated as a central driver of this toxicity, suggesting that epigenetic regulators may interfere with the pathological cardiac response. Here, we show that doxorubicin promotes topoisomerase IIb accumulation at cardiomyocyte-specific gene promoters (e.g., Actc1, Myl2, and Myh7) overlapping myocyte enhancer factor 2 binding sites and enhances myocyte enhancer factor 2 -dependent transcription. This response is attenuated by the pan-histone deacetylase inhibitor suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid -mediated cardioprotection requires class IIa histone deacetylases, as genetic loss of HDAC4 abolishes its effect. Mechanistically, suberoylanilide hydroxamic acid induces acetylation of the chaperone 14-3-3, disrupting its interaction with HDAC4/5, promoting their nuclear accumulation, and repressing myocyte enhancer factor 2 - driven transcription. In vivo, suberoylanilide hydroxamic acid mitigates doxorubicin-induced cardiotoxicity. These findings identify histone deacetylase inhibition as a cardioprotective repurposing strategy and reveal a mechanistic link between epigenetic regulation and anthracycline-associated cardiotoxicity.

Doxorubicin↗
PubMed2025

NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter.

Several autonomous mechanisms regulate protein expression, such as transcription, translation, post-translational modifications, and epigenetic changes. Rarely, these processes are controlled by the same molecular player with overlapping roles. Here, we reveal that transcription factor NFATc1 regulates both transcription and degradation of the Ca2+ channel Orai3 in a context-dependent manner. We demonstrate that NFATc1 drives Orai3 transcription in non-metastatic pancreatic cancer cells. In invasive and metastatic pancreatic cancer cells, NFATc1 induces Orai3 lysosomal degradation by transcriptionally enhancing MARCH8 E3-ubiquitin ligase. We show that MARCH8 physically interacts with Orai3 intracellular loop eventually resulting in its ubiquitination at the N-terminal. Mechanistically, the dichotomy in the regulation of Orai3 expression emerges from the differences in MARCH8 epigenetic landscape. We uncover that MARCH8 promoter is hyper-methylated in non-metastatic cells. Importantly, we demonstrate that MARCH8 restricts pancreatic cancer metastasis by targeting Orai3 degradation, thereby highlighting the pathophysiological importance of this signaling module. Taken together, we report a unique and clinically relevant scenario wherein the same transcription factor both enhances and curtails the expression of a target protein in cancer.

Humans↗