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At least 883 records · Page 49Linked to original sources
PubMed2006

Epigenetics: an emerging technology in the diagnosis and treatment of cancer.

Transcriptional silencing resulting from changes in epigenetic regulation of gene expression is the most frequent mechanism by which tumor suppressor genes are inactivated in human cancer. Genes participating in numerous functional groups and pathways leading to malignancy are subject to aberrant CpG methylation, with associated downregulation of expression, in human carcinogenesis. Methylation profiling can identify distinct subtypes of common human cancers and may have utility in predicting clinical phenotypes in individual patients, including sensitivity to chemotherapeutic agents. Hypomethylating agents have clinical activity in some hematological malignancies, and there is accumulating evidence correlating clinical response with demethylation and concomitant reactivation of expression of specific target genes. Epigenetic analysis is likely to have an increasingly important part to play in the diagnosis, prognostic assessment and treatment of malignant disease.

Animals↗
PubMed2005

Epigenetic therapy with decitabine for myelodysplasia and leukemia.

New therapeutic approaches are being developed for the treatment of cancer patients. Increasingly, drugs are being produced based on new insight into the intracellular processes in the cancer cell. Recently the typical epigenetic changes in the tumor cell have been considered as a therapeutic target. Several drugs have shown potential epigenetic activity. Decitabine (5-aza-2 -deoxycytidine, Dacogen) is one of the drugs that is able to induce changes in the methylation status of DNA. In this article the authors present an overview of this drug with regard to the chemistry, pharmacokinetics and the data that support its role as the new therapeutic agent in leukemia and myelodysplastic syndrome.

Animals↗
PubMed2005

A three-generation approach in biodemography is based on the developmental profiles and the epigenetics of female gametes.

We suggest that there are three premises underlying the need for biodemographic analyses of three-generations: 1.) To describe the structure of the genome, we need to use (apart from mutations) other kinds of heritable changes such as those mediated by facultative elements (variations) and epigenetic alterations. 2.) There are many reasons to analyze individual development and its deviations, such as the biodemographic perspective of fertilization - but also including all long-term intra-generational events of oogenesis and meiosis (beginning with the embryogenesis of the individual's mother - or during the grandmother's pregnancy). 3.) We need to explore the reality that every fertilized egg links - physically and genetically - three successive generations. We focus on genetic and epigenetic events, which start during egg cell lineage determination in F(n-2) gestation and which influence the developmental profile of F(n) generation cohorts. The three-generation approach in epidemiology and biodemography is important so that we might increase our understanding of the effects of environmental forces, such as viral epidemics, and of catastrophes, such as the Chernobyl accident. It is also important for evaluating the processes of senescence and the determinants of human disease.

Animals↗
PubMed2006

Plasma epigenetic markers for cancer detection and prenatal diagnosis.

Successful detection of circulating nucleic acids has opened up new possibilities in cancer testing and prenatal diagnosis. Circulating DNA markers are useful in cancer detection, prognostication and monitoring. Cancer-associated molecular changes which can be detected include gene mutations, chromosomal rearrangements, microsatellite alterations, viral sequences, and, to be discussed in more detailed, gene promoter hypermethylation. Methylation analysis is commonly performed by DNA digestion with methylation-sensitive restriction endonucleases followed by polymerase chain reaction (PCR), or bisulfite modification followed by methylation-specific PCR (MSP). The detection of fetal DNA in maternal plasma has opened up new possibilities for noninvasive prenatal diagnosis. However, circulating fetal DNA detection has been based on exploiting gender and polymorphic differences between the fetus and mother. The recent discovery of epigenetic differences between the maternal and the fetal DNA detectable in maternal plasma has launched a hunt for fetal-derived epigenetic markers in maternal plasma. It is hoped that this type of universally applicable markers would be made available in a clinical diagnostic setting in the near future.

DNA↗
PubMed1984

Epigenetic carcinogens: problems with identification and risk estimation.

The mechanisms of carcinogenesis are just beginning to be understood. There is recent interest in the broad classification of carcinogens into two categories based upon their mechanism of action: those that interact with DNA via a genetic mechanism are termed genetic carcinogens; and those that do not directly interact with DNA, but may cause changes in DNA tertiary structure or methylation patterns, and are termed epigenetic carcinogens. Present knowledge is inadequate to justify separate risk assessment methods for genetic vs. epigenetic carcinogens. Quantitative estimates of carcinogenic risk are currently best made using non-threshold models.

Animals↗
PubMed2000

Epigenetic alterations in methylation in oral squamous cell carcinoma cell lines detected by two-dimensional gel electrophoresis.

It has been described that DNA alterations in human oral squamous cell carcinomas were successfully demonstrated as 6 spots being commonly reduced in more than 50% of 10 lesions using the restriction landmark genomic scanning (RLGS) method. In the present study, the question of whether the DNA alterations involve not only genetic but also epigenetic change was examined with the use of cell lines Ca9-22, HO-1-u-1, HSC-2 and KB and treatment with a demethylating agent 5-aza-2'-deoxycytidine (5-AzaCDR). Intensities of two of the reduced spots were amplified in the cell lines by the 5-AzaCDR treatment, showing that they were due to altered DNA methylation. Our study provides clear evidence that epigenetic changes, like the methylation are related to carcinogenesis in human oral squamous cell epithelium.

Antimetabolites, Antineoplastic↗
PubMed2001

Evidence for epigenetic mechanisms that silence both basal and immune-stimulated transcription of the IL-8 gene.

It is becoming increasingly clear that epigenetic silencing of gene transcription plays a critical role in the regulation of gene expression in many biological processes. Tight regulation of immunomodulatory substances that are important for the initiation of the inflammatory cascade, such as chemoattractive cytokines, is essential to prevent initiation of unrestrained immune activation. Using the Caco-2 intestinal cell line as a model, we reveal two distinctly different mechanisms by which the gene for the neutrophil chemoattractive cytokine IL-8 is silenced. Nuclear run-on studies, as well as stably transfected reporter and marked minigene constructs, demonstrate that cellular differentiation inhibits immune-activated transcription of the IL-8 gene, a mechanism that is dependent on histone deacetylase activity. Unexpectedly, this silencing mechanism does not involve previously described regulatory elements in the IL-8 promoter but rather cis-acting regions located at a distance from the IL-8 gene locus. Genomic elements distant to the immediate IL-8 locus are also required to silence aberrant basal transcriptional activity of the IL-8 promoter in the absence of immune activation. However, in this case, silencing occurs in a histone deacetylase-independent fashion. These findings were confirmed in transgenic mice in which, in the absence of these elements, aberrant IL-8 gene activity was present primarily in the intestinal tract. Epigenetic silencing of cytokine gene transcription through distant genomic elements is an important level of gene regulation that may be relevant to the pathogenesis of immunologic disease states.

Animals↗
PubMed2004

Cutting Edge: Innate production of IFN-gamma by NK cells is independent of epigenetic modification of the IFN-gamma promoter.

The ability of NK and T cells to produce IFN-gamma is critical for resistance to numerous intracellular pathogens but the kinetics of these responses differ. Consistent with this is a requirement for naive T cells to become activated and undergo proliferation-dependent epigenetic changes to the IFN-gamma locus that allow them to produce IFN-gamma. The data presented here reveal that unlike T cells, murine NK cells produce IFN-gamma under conditions of short-term cytokine stimulation, and these events are independent of proliferation and cell cycle progression. Furthermore, analysis of the IFN-gamma locus in NK cells reveals that this locus is constitutively demethylated. The finding that NK cells do not need to remodel the IFN-gamma locus to produce IFN-gamma, either because they do not exhibit epigenetic repression or they have undergone prior remodeling during development, provides a molecular basis for the innate and adaptive regulation of the production of this cytokine.

Animals↗
PubMed2005

Signals from CD28 induce stable epigenetic modification of the IL-2 promoter.

CD28 costimulation controls multiple aspects of T cell function, including the expression of proinflammatory cytokine genes. One of these genes encodes IL-2, a growth factor that influences T cell proliferation, survival, and differentiation. Antigenic signaling in the absence of CD28 costimulation leads to anergy, a mechanism of tolerance that renders CD4+ T cells unable to produce IL-2. The molecular mechanisms by which CD28 costimulatory signals induce gene expression are not fully understood. In eukaryotic cells, the expression of many genes is influenced by their physical structure at the level of DNA methylation and local chromatin remodeling. To address whether these epigenetic mechanisms are operative during CD28-dependent gene expression in CD4+ T cells, we compared cytosine methylation and chromatin structure at the IL-2 locus in fully activated CD4+ effector T cells and CD4+ T cells rendered anergic by TCR ligation in the absence of CD28 costimulation. Costimulation through CD28 led to marked, stable histone acetylation and loss of cytosine methylation at the IL-2 promoter/enhancer. This was accompanied by extensive remodeling of the chromatin in this region to a structure highly accessible to DNA binding proteins. Conversely, TCR activation in the absence of CD28 costimulation was not sufficient to promote histone acetylation or cytosine demethylation, and the IL-2 promoter/enhancer in anergic cells remained completely inaccessible. These data suggest that CD28 may function through epigenetic mechanisms to promote CD4+ T cell responses.

Acetylation↗
PubMed2006

Epigenetic suppression of secreted frizzled related protein 1 (SFRP1) expression in human breast cancer.

Expression of Secreted frizzled related protein 1 (SFRP1), a recently identified tumor suppressor gene encoding a WNT signaling antagonist, has been found to be frequently down-regulated in breast cancer and is associated with disease progression and poor prognosis. Here, we investigated the role of epigenetic silencing of SFRP1 in breast cancer cell lines and primary breast tumors. Through analyses by methylation-specific PCR and bisulfite sequencing, promoter methylation of SFRP1 was detected in 88% (7/8) of breast cancer cell lines, 17% (1/6) of grade 1 of ductal carcinoma in situ (DCIS), 69% (9/13) of grade 2 and 3 of DCIS, 68% (19/28) of invasive ductal carcinomas (IDC) and 33% (6/18) of lobular carcinomas but not in any (0/14) of normal mammoplasty specimens and mammary epithelial organoids examined. Real-time RT-PCR studies indicated that loss or downregulation of SFRP1 expression in tumors is frequently associated with promoter hypermethylation. In addition, breast cancer cell lines with SFRP1 promoter hypermethylation reexpressed SFRP1 mRNA after treatment with 5-azaC, implying that DNA methylation is the predominant epigenetic mechanism for SFRP1 gene silencing. These findings suggest that frequent downregulation of SFRP1 expression in breast cancer can be attributed, in large part, to aberrant promoter hypermethylation in conjunction with or without histone deacetylation. Based on the frequency of tumor-specific hypermethylation in this gene, SFRP1 could provide a valuable marker for breast cancer.

Acetylation↗
PubMed2005

Chromatin remodeling by WSTF-ISWI at the replication site: opening a window of opportunity for epigenetic inheritance?

During DNA replication, chromatin states have to be accurately transmitted from the parental to the daughter strands for faithful epigenetic inheritance. Chromatin remodelling factors at the replication site are thought to be involved in this process. Recent work adds ATP-dependent nucleosome remodelling factors to this category of enzymes. The WICH complex, consisting of the ISWI-type ATPase SNF2H and the Williams Syndrome Transcription Factor (WSTF), binds to replication foci using PCNA, a key factor in DNA- and chromatin replication and DNA repair, as an interaction platform. Depletion of WSTF results in decreased chromatin accessibility, which is evident already in newly replicated DNA. This leads to heterochromatin formation on a global scale and a decrease in overall transcriptional activity. Here, we propose that WICH, by keeping nucleosomes mobile, provides access to the newly replicated DNA and may thereby create a window of opportunity after DNA replication for rebinding of factors that maintain the epigenetic state, and thus prevents aberrant heterochromatin formation. Our model may provide an explanation for the long-standing observation of a delay in chromatin "maturation" on newly replicated DNA, by connecting this delay with the action of PCNA-bound WSTF-ISWI, and highlights chromatin remodeling shortly after DNA replication as a critical point for regulation.

Adenosine Triphosphatases↗
PubMed2005

Maintenance of epigenetic memory in cloned embryos.

Different cell types have characteristic patterns of gene expression. Once a cell has differentiated, its daughter cells nearly always differentiate in the same way. The maintenance of cell lineage involves either instructions from a cell's surroundings or the inheritance of memory from a parent cell. In normal development, the differentiation state of a cell is remarkably stable and irreversible. However the transplantation of a somatic cell nucleus to an enucleated egg often leads to a complete reprogramming of gene expression. We summarize here the results of some Amphibian nuclear transfer experiments that reveal a memory of gene expression. This and some other experiments exemplify epigenetic memory that persists through many cell divisions. In the case of nuclear transfer experiments, the actively transcribed state of a gene can be propagated through many cell divisions in the absence of the stimulus that first induced the activity of this gene. We discuss the possible basis of these two examples of persistent epigenetic memory, namely changes at DNA methylation, and histone modifications.

Animals↗
PubMed2005

Epigenetic control of replication origins.

Efficient duplication of the eukaryotic genome requires the spatial and temporal coordination of numerous replication origins on each chromosome. Epigenetic factors, like chromatin environment, can have profound effects on origin site selection, utilization frequency, and cell cycle firing time. Precisely how chromatin contributes to origin site selection and timing is not completely understood. Recently, we reported on the cell cycle changes in chromatin structure at the plasmid replication origins of Epstein-Barr Virus (EBV) and Kaposi's Sarcoma-Associated Herpes virus (KSHV). These studies and others suggest that cell cycle changes in histone modification and nucleosome remodeling regulate prereplication factor assembly and initiation of DNA replication at origins. We discuss how these studies of viral origins may provide important insights into epigenetic control of cellular chromosome origins.

Epigenesis, Genetic↗
PubMed2006

Epigenetic inactivation implies a tumor suppressor function in hematologic malignancies for Polo-like kinase 2 but not Polo-like kinase 3.

The Polo-Like kinases (Plk) are a family of highly conserved cell cycle kinases, of which there are four members in humans. Whilst many studies support an oncogenic role for Plk1 in neoplasia, there is little definitive evidence at present to support involvement of the other family members in human cancer. Both Plk2 and Plk3 function in pathways of DNA damage response. Plk2 is a target gene for p53 and imposes a G2 checkpoint. More recent evidence reveals a novel function for Plk2 in mediating apoptosis in high grade B lymphomas. Epigenetic inactivation of Plk2 via aberrant CpG methylation in the transcriptional regulatory elements of the gene is a common event in B cell neoplasia, whereas epigenetic inactivation of Plk3 is exceedingly rare in lymphomas. Further, in every case lacking Plk2 expression, there is concomitant overexpression of Plk3, consistent with functional degeneracy between the two proteins. These results imply that Plk2 may function as a tumor suppressor in hematologic neoplasia and have pharmaco-epigenomic implications.

Animals↗
PubMed2005

A unified mode of epigenetic gene silencing: RNA meets polycomb group proteins.

Recently, an essential role for RNA in the epigenetic silencing of genes packaged within heterochromatin in animals has been recognized. The RNA appears to be involved in targeting chromatin remodeling activity to a specific locus and in later maintaining the repressed state of the gene. Epigenetic silencing of Hox cluster genes by the Polycomb group proteins also involves the formation of a stably inherited repressive chromatin structure. Recent studies of the C. elegans PcG gene sop-2 reveled an evolutionarily conserved property of PcG proteins in the binding of RNA, suggesting an important role for RNA in PcG-mediated Hox gene repression.

Animals↗
PubMed1999

Cutting edge: stable epigenetic inheritance of regional IFN-gamma promoter demethylation in CD44highCD8+ T lymphocytes.

Genomic DNA methylation patterns influence the development and maintenance of function during cellular differentiation. Methylation of regulatory sequences can have long-lasting effects on gene expression if inherited in an epigenetic manner. Recent work suggests that DNA methylation has a regulatory role in differential cytokine gene expression in primary T lymphocytes. Here we show, by clonal lineage analysis, that methylation patterns in the IFN-gamma promoter exhibit long term faithful inheritance in CD44highCD8+ T cells and their progeny, through 16 cell divisions and a clonal expansion of 5 orders of magnitude. Moreover, the demethylated IFN-gamma promoter is faithfully inherited following the withdrawal of T cell stimulation and the loss of detectable IFN-gamma mRNA, consistent with passive rather than active maintenance mechanisms. This represents a form of stable cellular memory, of defined epigenetic characteristics, that may contribute to the maintenance of T cell cytokine expression patterns and T cell memory.

Animals↗
PubMed2000

Human health consequences of environmentally-modulated gene expression: potential roles of ELF-EMF induced epigenetic versus mutagenic mechanisms of disease.

In order to determine if there might be biological and health consequences after exposures to extremely-low frequency electromagnetic fields (ELF-EMF), either experimentally or epidemiologically, mechanistic understanding of the potential means by which any environmental agent can affect cells in a multicellular organism has to be reviewed. The goal of this limited review is to demonstrate that, while the prevailing paradigm of the environmentally-induced acute and chronic diseases involves either cell killing (cytotoxicity) or gene/chromosome mutations (genotoxicity), alteration of the expression of genetic information at the transcriptional (turning genes "on" or "off"), translational (stabilizing or de-stabilizing the genetic message), or posttranslational (altering the gene product or protein) levels has the potential to contribute to various diseases. This latter mechanism, "epigenetic" toxicity, unlike the former two which are irreversible, is characterized by threshold-like action, multiple biochemical pathways and chronic, regular exposures to be effective. Ultimately, epigenetic toxicants affect one of four potential cell states, namely alteration of cell proliferation, cell differentiation, programmed cell death (apoptosis) or adaptive responses of differentiated cells.

DNA Damage↗
PubMed2000

Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer.

Mechanisms for multifocal bladder carcinogenesis remain unclear. To see whether normal mucosa had already acquired genetic or epigenetic changes, we examined loss of heterozygosity (LOH) at 10 microsatellite loci and methylation of the p16(INK4) CpG island in multiple tumors and pathologically normal mucosa in six patients with bladder cancer. Either LOH or methylation was detected in 77% of samples of normal epithelium, and LOH detected in samples of normal epithelium was also observed in most tumor samples. This result indicated that a population of cells in morphologically normal epithelium possessed genetic or epigenetic aberrations in common with bladder cancer, which might provide a ground for multiple tumorigenesis.

Aged↗