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Results for “epigenetic modification”

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At least 577 records · Page 32Linked to original sources
PubMed2003

A role for poly(ADP-ribosyl)ation in DNA methylation.

The aberrant DNA methylation of promoter regions of housekeeping genes leads to gene silencing. Additional epigenetic events, such as histone methylation and acetylation, also play a very important role in the definitive repression of gene expression by DNA methylation. If the aberrant DNA methylation of promoter regions is the starting or the secondary event leading to the gene silencing is still debated. Mechanisms controlling DNA methylation patterns do exist although they have not been ultimately proven. Our data suggest that poly(ADP-ribosyl)ation might be part of this control mechanism. Thus an additional epigenetic modification seems to be involved in maintaining tissue and cell-type methylation patterns that when formed during embryo development, have to be rigorously conserved in adult organisms.

Acetylation↗
PubMed2006

Regulation of Th2 differentiation and Il4 locus accessibility.

Helper T cells coordinate immune responses through the production of cytokines. Th2 cells express the closely linked Il4, Il13, and Il5 cytokine genes, whereas these same genes are silenced in the Th1 lineage. The Th1/Th2 lineage choice has become a textbook example for the regulation of cell differentiation, and recent discoveries have further refined and expanded our understanding of how Th2 differentiation is initiated and reinforced by signals from antigen-presenting cells and cytokine-driven feedback loops. Epigenetic changes that stabilize the active or silent state of the Il4 locus in differentiating helper T cells have been a major focus of recent research. Overall, the field is progressing toward an integrated model of the signaling and transcription factor networks, cis-regulatory elements, epigenetic modifications, and RNA interference mechanisms that converge to determine the lineage fate and gene expression patterns of differentiating helper T cells.

Animals↗
PubMed2004

A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring.

Epidemiological and animal studies suggest that diet-induced epigenetic modifications in early life can contribute to development of the metabolic syndrome in adulthood. We previously reported features of the metabolic syndrome in adult offspring of rats fed a diet rich in animal fat during pregnancy and suckling. We now report a study to compare the relative effects of high-fat feeding during 1) pregnancy and 2) the suckling period in the development of these disorders. As observed previously, 6-mo-old female offspring of fat-fed dams suckled by the same fat-fed dams (OHF) demonstrated raised blood pressure, despite being fed a balanced diet from weaning. Female offspring of fat-fed dams "cross fostered" to dams consuming a control diet during suckling (OHF/C) demonstrated raised blood pressure compared with controls (OC) [systolic blood pressure (SBP; mmHg) means +/- SE: OHF/C, 132.5 +/- 3.0, n = 6 vs. OC, 119.0 +/- 3.8, n = 7, P < 0.05]. Female offspring of controls cross fostered to dams consuming the fat diet (OC/HF) were also hypertensive [SBP (mmHg) 131.0 +/- 2.5 mmHg, n = 6 vs. OC, P < 0.05]. Endothelium-dependent relaxation (EDR) of male and female OHF and OHF/C mesenteric small arteries was similar and blunted compared with OC (P < 0.001). OC/HF arteries showed profoundly impaired EDR (OC/HF vs. OHF, P < 0.001). OHF/C and OC/HF demonstrated hyperinsulinemia and increased adiposity. Features of the metabolic syndrome in adult offspring of fat-fed rats can be acquired both antenatally and during suckling. However, exposure during pregnancy confers adaptive protection against endothelial dysfunction induced by maternal fat feeding during suckling.

Animals↗
PubMed2006

Identification of a gene network contributing to hypertrophy in callipyge skeletal muscle.

The callipyge mutation in sheep results in postnatal skeletal muscle hypertrophy in the pelvic limbs and loins with little or no effect on anterior skeletal muscles. Associated with the phenotype are changes in the expression of a number of imprinted genes flanking the site of the mutation, which lies in an intergenic region at the telomeric end of ovine chromosome 18. The manner in which these local changes in gene expression are translated into muscle hypertrophy is not known. Microarray-based transcriptional profiling was used to identify differentially expressed genes in longissimus dorsi skeletal muscle samples taken at birth and 12 wk of age from callipyge and wild-type sheep. The phenotype was only expressed at the latter developmental time and associated with decreased type 1 fibers (slow oxidative) and a shift toward type IIx and IIb fibers (fast-twitch glycolytic). We have identified 131 genes in the samples taken at 12 wk of age that were differentially expressed as a function of genotype but not due to the fiber type changes. The gene expression changes occurring as a function of genotype in the samples taken at birth indicated that the transcriptional framework underpinning the phenotype was emerging prior to expression of the phenotype. Eight genes were differentially expressed as a function of genotype at both developmental times. A model is proposed describing a core network of genes and histone epigenetic modifications that is likely to underpin the fiber type changes and muscle hypertrophy characteristic of callipyge sheep.

Animals↗
PubMed2006

Inhibition of DNA methyltransferase activity prevents tumorigenesis in a mouse model of prostate cancer.

Transcriptional silencing of tumor suppressor genes by DNA methylation plays an important role in tumorigenesis. These aberrant epigenetic modifications may be mediated in part by elevated DNA methyltransferase levels. DNA methyltransferase 1 (DNMT1), in particular, is overexpressed in many tumor types. Recently, we showed that Dnmt1 is transcriptionally regulated by E2F transcription factors and that retinoblastoma protein (pRb) inactivation induces Dnmt1. Based on these observations, we investigated regulation of Dnmt1 by polyomavirus oncogenes, which potently inhibit the pRb pocket protein family. Infection of primary human prostate epithelial cells with BK polyomavirus dramatically induced Dnmt1 transcription following large T antigen (TAg) translation and E2F activation. For in vivo study of Dnmt1 regulation, we used the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which expresses the SV40 polyomavirus early region, including TAg, under control of a prostate-specific promoter. Analysis of TRAMP prostate lesions revealed greatly elevated Dnmt1 mRNA and protein levels beginning in prostatic intraepithelial neoplasia and continuing through advanced prostate cancer and metastasis. Interestingly, when TRAMP mice were treated in a chemopreventive manner with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza), 0 of 14 mice developed prostate cancer at 24 weeks of age, whereas 7 of 13 (54%) control-treated mice developed poorly differentiated prostate cancer. Treatment with 5-aza also prevented the development of lymph node metastases and dramatically extended survival compared with control-treated mice. Taken together, these data suggest that Dnmt1 is rapidly activated by pRb pathway inactivation, and that DNA methyltransferase activity is required for malignant transformation and tumorigenesis.

Animals↗
PubMed2006

Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members.

The breast cancer-associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Delta11/Delta11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging.

Animals↗
PubMed2006

Cytosine methylation profiles as a molecular marker in non-small cell lung cancer.

Aberrant promoter methylation is frequently observed in different types of lung cancer. Epigenetic modifications are believed to occur before the clinical onset of the disease and hence hold a great promise as early detection markers. Extensive analysis of DNA methylation has been impeded by methods that are either too labor intensive to allow large-scale studies or not sufficiently quantitative to measure subtle changes in the degree of methylation. We used a novel quantitative DNA methylation analysis technology to complete a large-scale cytosine methylation profiling study involving 47 gene promoter regions in 96 lung cancer patients. Each individual contributed a lung cancer specimen and corresponding adjacent normal tissue. The study identified six genes with statistically significant differences in methylation between normal and tumor tissue (P < 10(-6)). We explored the quantitative methylation data using an unsupervised hierarchical clustering algorithm. The data analysis revealed that methylation patterns differentiate normal from tumor tissue. For validation of our approach, we divided the samples to train a classifier and test its performance. We were able to distinguish normal from lung cancer tissue with >95% sensitivity and specificity. These results show that quantitative cytosine methylation profiling can be used to identify molecular classification markers in lung cancer.

Biomarkers, Tumor↗
PubMed2002

Escape from X inactivation.

Although the process of X inactivation in mammalian cells silences the majority of genes on the inactivated X chromosome, some genes escape this chromosome-wide silencing. Genes that escape X inactivation present a unique opportunity to study the process of silencing and the mechanisms that protect some genes from being turned off. In this review, we will discuss evolutionary aspects of escape from X inactivation, in relation to the divergence of the sex chromosomes. Molecular characteristics, expression, and epigenetic modifications of genes that escape will be presented, including their developmental regulation and the implications of chromatin domains along the X chromosome in modeling the escape process.

Animals↗
PubMed2005

Genome evolution of allopolyploids: a process of cytological and genetic diploidization.

Allopolyploidy is a prominent mode of speciation in higher plants. Due to the coexistence of closely related genomes, a successful allopolyploid must have the ability to invoke and maintain diploid-like behavior, both cytologically and genetically. Recent studies on natural and synthetic allopolyploids have raised many discrepancies. Most species have displayed non-Mendelian behavior in the allopolyploids, but others have not. Some species have demonstrated rapid genome changes following allopolyploid formation, while others have conserved progenitor genomes. Some have displayed directed, non-random genome changes, whereas others have shown random changes. Some of the genomic changes have appeared in the F1 hybrids, which have been attributed to the union of gametes from different progenitors, while other changes have occurred during or after genome doubling. Although these observations provide significant novel insights into the evolution of allopolyploids, the overall mechanisms of the event are still elusive. It appears that both genetic and epigenetic operations are involved in the diploidization process of allopolyploids. Overall, genetic and epigenetic variations are often associated with the activities of repetitive sequences and transposon elements. Specifically, genomic sequence elimination and chromosome rearrangement are probably the major forces guiding cytological diploidization. Gene non-functionalization, sub-functionalization, neo-functionalization, as well as other kinds of epigenetic modifications, are likely the leading factors promoting genetic diploidization.

Chromosomes, Plant↗
PubMed2006

Genomic imprinting is a barrier to parthenogenesis in mammals.

Only mammals have relinquished parthenogenesis as a means of producing descendants. Bi-parental reproduction is necessary due to parent-specific epigenetic modification of the genome during gametogenesis, which leads to non-equivalent expression of imprinted genes from the maternal and paternal alleles. However, a series of our work showed that alteration of maternal imprinting by oocyte reconstruction using non-growing oocytes, together with deletion of the H19 gene provide appropriate expression of imprinted genes from the maternal genome. The resulting ng (non-growing)/fg (fully-grown) parthenogenic embryos were developed to term. Here, we discuss how the parthenogenetic embryos survived as normal individuals.

Animals↗
PubMed2006

Repetitive elements in imprinted genes.

Genomic imprinting in mammals results in mono-allelic expression of about 80 genes depending on the parental origin of the alleles. Though the epigenetic mechanisms underlying imprinting are rather clear, little is known about the genetic basis for these epigenetic mechanisms. It is still rather enigmatic which sequence features discriminate imprinted from non-imprinted genes/regions and why and how certain sequence elements are recognized and differentially marked in the germlines. It seems likely that specific DNA elements serve as signatures that guide the necessary epigenetic modification machineries to the imprinted regions. Inter- and intraspecific comparative genomic studies suggest that the unusual occurrence and distribution of various types of repetitive elements within imprinted regions may represent such genomic imprinting signatures. In this review we summarize the various observations made and discuss them in light of experimental data.

Animals↗
PubMed2006

Genome-wide survey of imprinted genes.

The developmental failure of mammalian parthenogenote has been a mystery for a long time and posed a question as to why bi-parental reproduction is necessary for development to term. In the 1980s, it was proven that this failure was not due to the genetic information itself, but to epigenetic modification of genomic DNA. In the following decade, several studies successfully identified imprinted genes which were differentially expressed in a parent-of-origin-specific manner, and it was shown that the differential expression depended on the pattern of DNA methylation. These facts prompted development of genome-wide systematic screening methods based on DNA methylation and differential gene expression to identify imprinted genes. Recently computational approaches and microarray technology have been introduced to identify imprinted genes/loci, contributing to the expansion of our knowledge. However, it has been shown that the gene silencing derived from genomic imprinting is accomplished by several mechanisms in addition to direct DNA methylation, indicating that novel approaches are further required for comprehensive understanding of genomic imprinting. To unveil the mechanism of developmental failure in mammalian parthenogenote, systematic screenings for imprinted genes/loci have been developed. In this review, we describe genomic imprinting focusing on the history of genome-wide screening.

Animals↗
PubMed2006

Imprinting in neurons.

Although most imprinted genes display parent-origin-specific gene expression in tissues where they are transcribed, some genes are imprinted in a tissue-specific manner. Genes that show brain-specific imprinting or brain-specific lack of imprinting present a unique opportunity to study the process of imprinting during tissue differentiation. In this review, I introduce the systematic study of brain-cell-lineage-specific imprinting using a primary brain cell culture system, where neurons or glial cells are cultured separately. Two reports using the primary brain cell culture revealed brain-cell-lineage-specific imprinting in Ube3a and Igf2r, which had previously been described to show brain-specific imprinting and brain-specific lack of imprinting, respectively. Such brain-cell-lineage-specific imprinting was associated with cell-specific epigenetic modifications, especially with their reciprocally imprinted antisense non-coding RNAs, Ube3a-ATS and Air. These results emphasize the necessity of imprinting analysis at the cell level rather than in whole brain tissue during brain differentiation. The brain cell culture system provides us with a new powerful tool to understand the molecular mechanism of brain-specific imprinting.

Animals↗
PubMed2006

Mutagenesis in mice of nuclear hormone receptor binding sites in the Igf2/H19 imprinting control region.

The H19/Igf2 imprinting control region (ICR) is a DNA methylation-dependent chromatin insulator in somatic cells. The hypomethylated maternally inherited ICR binds the insulator protein CTCF at four sites, and blocks activity of the proximal Igf2 promoter by insulating it from the shared distal enhancers. The hypermethylated paternally inherited ICR lacks CTCF binding and insulator activity, but induces methylation-silencing of the paternal H19 promoter. The paternal-specific methylation of the ICR is established in the male germ cells, while the ICR emerges from the female germ line in an unmethylated form. Despite several attempts to find cis-regulatory elements, it is still unknown what determines these male and female germ cell-specific epigenetic modifications. We recently proposed that five in vivo footprints spanning fifteen half nuclear hormone receptor (NHR) binding sites within the ICR might be involved, and here we report on the effects of mutagenizing all of these half sites in mice. No effect was obtained--in the female and male germ lines the mutant ICR remained hypomethylated and hypermethylated, respectively. The ICR imprinting mechanism remains undefined.

Animals↗
PubMed2006

Imprinted genes, placental development and fetal growth.

In mammals, imprinted genes have an important role in feto-placental development. They affect the growth, morphology and nutrient transfer capacity of the placenta and, thereby, control the nutrient supply for fetal growth. In particular, the reciprocally imprinted Igf2-H19 gene complex has a central role in these processes and matches the placental nutrient supply to the fetal nutrient demands for growth. Comparison of Igf2P0 and complete Igf2 null mice has shown that interplay between placental and fetal Igf2 regulates both placental growth and nutrient transporter abundance. In turn, epigenetic modification of imprinted genes via changes in DNA methylation may provide a mechanism linking environmental cues to placental phenotype, with consequences for development both before and after birth. Changes in expression of imprinted genes, therefore, have major implications for developmental programming and may explain the poor prognosis of the infant born small for gestational age and the wide spectrum of adult-onset diseases that originate in utero.

Animals↗
PubMed2005

Genome-wide screening for target regions of histone deacetylases in cardiomyocytes.

The acetylation status of core histones in cardiomyocytes has been linked to the development of cardiac hypertrophy and heart failure. Little is known, however, of the genes affected by abnormal histone acetylation in such pathological conditions. We recently developed a genome-wide screening method, differential chromatin scanning (DCS), to isolate genomic fragments associated with histones subject to differential acetylation. We have now applied DCS to H9C2 rat embryonic cardiomyocytes incubated with or without trichostatin A (TSA), a specific inhibitor of histone deacetylase (HDAC) activity. About 200 genomic fragments were readily isolated by DCS on the basis of the preferential acetylation of associated histones in TSA-treated cells. Quantitation of the amount of DNA in chromatin immunoprecipitates prepared with antibodies to acetylated histone H3 revealed that 37 of 38 randomly chosen DCS clones were preferentially precipitated from the TSA-treated cells, thus verifying the high fidelity of DCS. Epigenetic regulation of DCS clones was further confirmed in cells treated with sodium butyrate, another HDAC inhibitor, as well as in cardiac myocytes isolated from neonatal rats. The mRNA level of 9 (39%) of 23 genes corresponding to DCS clones changed in parallel with the level of histone acetylation in H9C2 cells. Furthermore, a physiological hypertrophic stimulus, cardiotrophin-1, affected the acetylation level of histones associated with genomic regions corresponding to certain DCS clones. Our data thus establish a genome-wide profile of HDAC targets in cardiomyocytes, which should provide a basis for further investigations into the role of epigenetic modification in cardiac disorders.

Acetylation↗
PubMed2002

High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease.

Anaplastic large cell lymphoma (ALCL) with t(2;5)(p23;q35) and Hodgkin disease (HD) share many cellular features, including expression of CD30. We compared gene expression profiles of 4 ALCL (Karpas 299, SU-DHL-1, DEL, SR-786) and 3 HD cell lines and found that BCL3, which encodes a nuclear protein belonging to the I kappa B family of inhibitors of nuclear factor-kappa B (NF-kappa B) transcriptional factors, was expressed at higher levels in ALCL than HD. Northern and Western blotting analyses confirmed the high-level expression of BCL3 in ALCL at both mRNA and protein levels. We established a real-time reverse transcriptase-mediated polymerase chain reaction assay to measure the BCL3 mRNA level and found a predominant level of BCL3 expression in t(2;5)(+) ALCL; the levels of cell lines and clinical materials were comparable to or higher than that of a B-cell chronic lymphocytic leukemia carrying t(14;19)(q32;q13). Southern blotting and fluorescence in situ hybridization disclosed that the BCL3 gene copies were amplified in SU-DHL-1, whereas Karpas 299 carried 4 BCL3 gene loci. The BCL3 gene contains 2 cytosine-guanine dinucleotide (CpG) islands, and the intragenic 3' CpG was entirely demethylated in SU-DHL-1 and DEL. In contrast to HD, in which NF-kappa B was constitutively activated, ALCL cells consistently showed (p50)(2) homodimer binding activity on electrophoretic mobility shift assay. It is suggested that the high-level nuclear Bcl-3 sequesters the (p50)(2) homodimer to the nucleus, which may account for the contradictory effect of CD30 stimulation on ALCL and HD. We propose that BCL3 is overexpressed by genetic and epigenetic modifications, potentially contributing to the development of t(2;5)(+) ALCL.

B-Cell Lymphoma 3 Protein↗
PubMed2005

Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma.

Many B-lineage-specific genes are down-regulated in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We investigated the involvement of epigenetic modifications in gene silencing in cHL cell lines and in microdissected primary HRS cells. We assessed the expression and methylation status of CD19, CD20, CD79B, SYK, PU.1, BOB.1/OBF.1, BCMA, and LCK, all of which are typically down-regulated in cHL. We could reactivate gene expression in cHL cell lines with the DNA demethylating agent 5-aza-deoxycytidine (5-aza-dC). Using methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and digestion with methylation-sensitive endonuclease followed by polymerase chain reaction (PCR), we determined the methylation status of promoter regions of PU.1, BOB.1/OBF.1, CD19, SYK, and CD79B. Down-regulation of transcription typically correlated with hypermethylation. Using bisulfite genomic sequencing we found that in microdissected HRS cells of primary cHL SYK, BOB.1/OBF.1, and CD79B promoters were also hypermethylated. Ectopic expression of both Oct2 and PU.1 in a cHL cell line potentiated endogenous PU.1 and SYK expression after 5-aza-dC treatment. These observations indicate that silencing of the B-cell-specific genes in cHL may be the consequence of a compromised regulatory network where down-regulation of a few master transcription factors results in silencing of numerous genes.

Azacitidine↗