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PubMed2005

Overview of cancer epigenetics.

Epigenetic mechanisms including DNA and histone modifications result in silencing of genes without changing the coding sequence of the gene. Even though these events are heritable, they are potentially reversible, thus opening up opportunities for therapeutic intervention. The importance of epigenetic changes in human cancer is only now being recognized in the medical community. A series of discoveries over the last four decades has thrust epigenetics into the forefront of new drug discoveries. Three systems--DNA methylation, RNA-associated silencing, and histone modification--are used to initiate and sustain epigenetic silencing. Current knowledge suggests that agents that intervene in this process by "turning back on" silenced genes may represent a significant advancement in treating many forms of cancer. In addition, changed patterns of methylation can be detected with a high degree of sensitivity thus providing clinicians with prognostic information.

DNA Methylation↗
PubMed2002

The many faces of histone lysine methylation.

Diverse post-translational modifications of histone amino termini represent an important epigenetic mechanism for the organisation of chromatin structure and the regulation of gene activity. Within the past two years, great progress has been made in understanding the functional implications of histone methylation; in particular through the characterisation of histone methyltransferases that direct the site-specific methylation of, for example, lysine 9 and lysine 4 positions in the histone H3 amino terminus. All known histone methyltransferases of this type contain the evolutionarily conserved SET domain and appear to be able to stimulate either gene repression or gene activation. Methylation of H3 Lys9 and Lys4 has been visualised in native chromatin, indicating opposite roles in structuring repressive or accessible chromatin domains. For example, at the mating-type loci in Schizosaccharomyces pombe, at pericentric heterochromatin and at the inactive X chromosome in mammals, striking differences between these distinct marks have been observed. H3 Lys9 methylation is also important to direct additional epigenetic signals such as DNA methylation--for example, in Neurospora crassa and in Arabidopsis thaliana. Together, the available data strongly establish histone lysine methylation as a central modification for the epigenetic organisation of eukaryotic genomes.

Animals↗
PubMed2002

Epigenetics in cancer: implications for early detection and prevention.

Knowledge of the molecular events that occur during the early stages of cancer has advanced rapidly. The initiation and development of cancer involves several molecular changes, which include epigenetic alterations. Epigenetics is the study of modifications in gene expression that do not involve changes in DNA nucleotide sequences. Modifications in gene expression through methylation of DNA and remodelling of chromatin via histone proteins are believed to be the most important of the epigenetic changes. The study of epigenetics offers great potential for the identification of biomarkers that can be used to detect and diagnose cancer in its earliest stages and to accurately assess individual risk. There has been a recent surge of interest among researchers as variations in the methylation of DNA have been shown to be the most consistent molecular changes in many neoplasms. An important distinction between a genetic and an epigenetic change in cancer is that epigenetic changes can be reversed more easily by use of therapeutic interventions. The discovery of these basic premises should stimulate much future research on epigenetics.

Cell Transformation, Neoplastic↗
PubMed2006

How is epigenetic information on chromatin inherited after DNA replication?

Although most somatic cells have identical genetic information, gene expression profiles are quite distinct in each cell type. The gene expression profiles are considered to be determined mainly by chromatin-encoded epigenetic information that includes histone modifications, histone variants, and factors such as HP1 and polycomb group proteins that organize higher-ordered chromatin structures. To gain insights into how such epigenetic information on chromatin is inherited on daughter DNA strands after DNA replication, we have purified the preassembled form of histone H3 by immunoaffinity purification. The histone H3 complex contains the two histone H3-H4 chaperones CAF1 and ASF1. Surprisingly, the H3 complex also contains a pair of H3-H4 dimers. This observation is striking because histones H3-H4 are known to exist as tetramers in solution. Since histones H3-H4 in the predeposition complex exist as a dimer, this raises the possibility that the H3-H4 dimer in the complex pairs with a parental H3-H4 dimer, assembling the de novo-synthesized and parental H3-H4 dimers in the same nucleosome. Based on these results, we propose a semi-conservative model of nucleosome duplication, which allows for segregation of parental H3-H4 dimers with encoded epigenetic information evenly to daughter DNA strands.

Animals↗
PubMed2006

Epigenetic acquisition of inducibility of type III cytotoxicity in P. aeruginosa.

BACKGROUND: Pseudomonas aeruginosa, an opportunistic pathogen, is often encountered in chronic lung diseases such as cystic fibrosis or chronic obstructive pneumonia, as well as acute settings like mechanical ventilation acquired pneumonia or neutropenic patients. It is a major cause of mortality and morbidity in these diseases. In lungs, P. aeruginosa settles in a biofilm mode of growth with the secretion of exopolysaccharides in which it is encapsulated, enhancing its antibiotic resistance and contributing to the respiratory deficiency of patients. However, bacteria must first multiply to a high density and display a cytotoxic phenotype to avoid the host's defences. A virulence determinant implicated in this step of infection is the type III secretion system (TTSS), allowing toxin injection directly into host cells. At the beginning of the infection, most strains isolated from patients' lungs possess an inducible TTSS allowing toxins injection or secretion upon in vivo or in vitro activation signals. As the infection persists most of the bacteria permanently loose this capacity, although no mutations have been evidenced. We name "non inducible" this phenotype. As suggested by the presence of a positive feedback circuit in the regulatory network controlling TTSS expression, it may be due to an epigenetic switch allowing heritable phenotypic modifications without genotype's mutations. RESULTS: Using the generalised logical method, we designed a minimal model of the TTSS regulatory network that could support the epigenetic hypothesis, and studied its dynamics which helped to define a discriminating experimental scenario sufficient to validate the epigenetic hypothesis. A mathematical framework based on formal methods from computer science allowed a rigorous validation and certification of parameters of this model leading to epigenetic behaviour. Then, we demonstrated that a non inducible strain of P. aeruginosa can stably acquire the capacity to be induced by calcium depletion for the TTSS after a short pulse of a regulatory protein. Finally, the increased cytotoxicity of a strain after this epigenetic switch was demonstrated in vivo in an acute pulmonary infection model. CONCLUSION: These results may offer new perspectives for therapeutic strategies to prevent lethal infections by P. aeruginosa by reverting the epigenetic inducibility of type III cytotoxicity.

Bacterial Proteins↗
PubMed2004

The roles of histone modifications and small RNA in centromere function.

Here, epigenetic regulation of centromeric chromatin in fission yeast (Schizosaccharomyces pombe) is reviewed, focussing on the role of histone modifications and the link to RNA interference (RNAi). Fission yeast centromeres are organized into two structurally and functionally distinct domains, both of which are required for centromere function. The central core domain anchors the kinetochore structure while the flanking heterochromatin domain is important for sister centromere cohesion. The chromatin structure of both domains is regulated epigenetically. In the central core domain, the histone H3 variant Cnp1(CENP-A) plays a key role. In the flanking heterochromatin domain, histones are kept underacetylated by the histone deacetylases (HDACs) Clr3, Clr6 and Sir2, and methylated by Clr4 methyltransferase (HMTase) to create a specific binding site for the Swi6 protein. Swi6 then directly mediates cohesin binding to the centromeric heterochromatin. Recently, a surprising link was made between heterochromatin formation and RNAi.

Centromere↗
PubMed2005

Epigenetics of cervical cancer. An overview and therapeutic perspectives.

Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissues after treatment with demethylating and histone deacetylase inhibitors. In addition, detection of epigenetic changes in cytological smears, serum DNA, and peripheral blood are of potential interest for development of novel biomolecular markers for early detection, prediction of response, and prognosis.

Animals↗
PubMed2004

REST and peace for the neuronal-specific transcriptional program.

Despite a genetic homogeneity, cells in multicellular organisms are structurally and functionally heterogeneous. The diversity of cell phenotypes exists due to differential transcriptional programs precisely regulated by specific nuclear factors and induced upon differentiation. The differences in gene expression programs arise during development and become heritable during cell proliferation. Over the last few years, research has focused on three molecular mechanisms that mediate epigenetic phenomena: DNA methylation, histone modification, and formation of specialized nuclear domains or territories. All of these processes are dynamic and tightly linked to the organism's development. Here we review advances in understanding the significance of epigenetic mechanisms in the establishment and maintenance of the specialized transcriptional program. We project the accumulated knowledge onto the delineation of the molecular mechanisms by which central nervous system-specific genes are expressed in the nervous system and repressed in other tissues.

Animals↗
PubMed2001

Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin.

Post-translational modifications of histone amino termini are an important regulatory mechanism that induce transitions in chromatin structure, thereby contributing to epigenetic gene control and the assembly of specialized chromosomal subdomains. Methylation of histone H3 at lysine 9 (H3-Lys9) by site-specific histone methyltransferases (Suv39h HMTases) marks constitutive heterochromatin. Here, we show that H3-Lys9 methylation also occurs in facultative heterochromatin of the inactive X chromosome (Xi) in female mammals. H3-Lys9 methylation is retained through mitosis, indicating that it might provide an epigenetic imprint for the maintenance of the inactive state. Disruption of the two mouse Suv39h HMTases abolishes H3-Lys9 methylation of constitutive heterochromatin but not that of the Xi. In addition, HP1 proteins, which normally associate with heterochromatin, do not accumulate with the Xi. These observations suggest the existence of an Suv39h-HP1-independent pathway regulating H3-Lys9 methylation of facultative heterochromatin.

Amniocentesis↗
PubMed2005

[Epigenome and cancer: new possibilities of cancer prevention and therapy?].

In recent years it became evident that epigenetic control of gene expression plays important role in the development of cancer. Epigenetic alterations occur throughout all stages of carcinogenesis, what makes them excellent targets for both chemoprevention and, at later stages, chemotherapy. Two changes integral to epigenetic transcriptional control are DNA methylation and covalent modifications of histone proteins. In cancer cells, genome-wide hypomethylation is accompanied by local DNA hypermethylation with unique patterns exhibited by each tumor type. Hypermethylation of promoter regions of classic tumor suppressor genes in human cancers is at least as common as mutation as a mechanism for their inactivation. The second major layer of epigenetic transcriptional control is modification of histone proteins, particularly their acetylation. These two ways of epigenetic control are integrally linked. In this review we summarize the current knowledge about epigenetic events related to cancer and discuss the possibility of using them as chemotherapy or chemoprevention targets.

Animals↗
PubMed2001

Modifications of the histone N-terminal domains. Evidence for an "epigenetic code"?

A multicellular organism is made up of a variety of different cell types and tissues. This organization is accomplished by a well-concerted action of different regulatory molecules, which--in a very hierarchical manner--influence the expression of certain cell-specific genes. Many of those regulators are transcription factors, which directly influence the expression of the controlled gene by binding to a specific DNA sequence within its promoter or enhancer region. This binding then leads to an enhancement or a decrease in the rate of transcription of that particular gene and eventually regulates the production of the corresponding polypeptide. One major obstacle to the binding of these transcription factors is the fact that DNA is not readily accessible in the eukaryotic nucleus. It is associated with a class of very basic proteins called histones. This complex of histones and DNA is called chromatin.

Animals↗
PubMed2004

Future potential of the Human Epigenome Project.

Deciphering the information encoded in the human genome is key for the further understanding of human biology, physiology and evolution. With the draft sequence of the human genome completed, elucidation of the epigenetic information layer of the human genome becomes accessible. Epigenetic mechanisms are mediated by either chemical modifications of the DNA itself or by modifications of proteins that are closely associated with DNA. Defects of the epigenetic regulation involved in processes such as imprinting, X chromosome inactivation, transcriptional control of genes, as well as mutations affecting DNA methylation enzymes, contribute fundamentally to the etiology of many human diseases. Headed by the Human Epigenome Consortium, the Human Epigenome Project is a joint effort by an international collaboration that aims to identify, catalog and interpret genome-wide DNA methylation patterns of all human genes in all major tissues. Methylation variable positions are thought to reflect gene activity, tissue type and disease state, and are useful epigenetic markers revealing the dynamic state of the genome. Like single nucleotide polymorphisms, methylation variable positions will greatly advance our ability to elucidate and diagnose the molecular basis of human diseases.

CpG Islands↗
PubMed2006

HP1 proteins are essential for a dynamic nuclear response that rescues the function of perturbed heterochromatin in primary human cells.

Cellular information is encoded genetically in the DNA nucleotide sequence and epigenetically by the "histone code," DNA methylation, and higher-order packaging of DNA into chromatin. Cells possess intricate mechanisms to sense and repair damage to DNA and the genetic code. However, nothing is known of the mechanisms, if any, that repair and/or compensate for damage to epigenetically encoded information, predicted to result from perturbation of DNA and histone modifications or other changes in chromatin structure. Here we show that primary human cells respond to a variety of small molecules that perturb DNA and histone modifications by recruiting HP1 proteins to sites of altered pericentromeric heterochromatin. This response is essential to maintain the HP1-binding kinetochore protein hMis12 at kinetochores and to suppress catastrophic mitotic defects. Recruitment of HP1 proteins to pericentromeres depends on histone H3.3 variant deposition, mediated by the HIRA histone chaperone. These data indicate that defects in pericentromeric epigenetic heterochromatin modifications initiate a dynamic HP1-dependent response that rescues pericentromeric heterochromatin function and is essential for viable progression through mitosis.

Cell Cycle Proteins↗
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↗
PubMed2003

Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.

Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.

Aging↗
PubMed2005

Dynamic lysine methylation on histone H3 defines the regulatory phase of gene transcription.

Covalent modifications to histones are key epigenetic marks that control gene transcription. Multiple lysine residues on histone H3 are methylated (me), but their functions are unclear. Here, we demonstrate two phases of combinatorial and dynamic H3 methylation during induction of transcription at MET16 in yeast. K4me3 with K36me2/3 define a postinitiation regulatory phase and precede the appearance of K4me2 with K79me2 at the onset of transcript elongation. The Isw1 ATPase delays the release of initiated RNA polymerase II (RNAPII) into elongation to facilitate chromatin modifications. The Spp1 subunit of complex associated with Set1 (COMPASS) and Set2, determining K4me3 and K36me2/3, respectively, are required for transient NuA4-dependent H4K8ac. This releases RNAPII from Isw1 control and promotes controlled transcription elongation and termination. We propose that newly initiated RNAPII is under epigenetic control.

DNA, Fungal↗
PubMed2003

Epigenetic dynamics of imprinted X inactivation during early mouse development.

The initiation of X-chromosome inactivation is thought to be tightly correlated with early differentiation events during mouse development. Here, we show that although initially active, the paternal X chromosome undergoes imprinted inactivation from the cleavage stages, well before cellular differentiation. A reversal of the inactive state, with a loss of epigenetic marks such as histone modifications and polycomb proteins, subsequently occurs in cells of the inner cell mass (ICM), which give rise to the embryo-proper in which random X inactivation is known to occur. This reveals the remarkable plasticity of the X-inactivation process during preimplantation development and underlines the importance of the ICM in global reprogramming of epigenetic marks in the early embryo.

Acetylation↗
PubMed2025

Genetic and Epigenetic Approaches to Opioid Use Disorder.

BACKGROUND: Opioid use disorder (OUD) is a major global-scale social issue affecting public health. The high potential for addiction and dependence makes opioid use a significant concern, contributing to substance-related disorders. Both genetic and environmental factors contribute to the predisposition to OUD, with the opioidergic, dopaminergic, and GABAergic systems playing primary roles in itsonset. METHODS: This narrative review documents the association between genes and their variants related to these three systems, along with current evidence on epigenetic interventions in OUD. Relevant studies investigating candidate-gene associations and molecular mechanisms were synthesized to highlight genetic variants and epigenetic processes linked to OUD. RESULTS: Genetic associations play a prominent role in OUD, with several single-nucleotide variants identified in affected populations. Key genes implicated include OPRM1, OPRD1, OPRK1, PDYN, OPRL1, and POMC from the opioidergic system; DRD1, DRD2, DRD3, DRD4, ANKK1, and COMT from the dopaminergic system; and GABRA2, GABRB3, GABRG2, GAD1, and GAD2 from the GABAergic system. Evidence also indicates that chronic opioid use is associated with epigenetic changes through posttranslational histone modifications and DNA methylation. However, limitations in existing studies include small sample sizes, limited replication, and potential stratification biases. CONCLUSIONS: Although many candidate-gene associations have been proposed for OUD, robust evidence remains limited. Large, ancestrally diverse genome-wide association studies (GWAS) and systematic replication studies are urgently needed. A deeper understanding of the genetic, epigenetic, and neurobiological bases of addiction will be essential for the development of precisely targeted medications to improve prevention and treatment outcomes for OUD.

Humans↗