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At least 757 records · Page 42Linked to original sources
PubMed2002

Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+].

The yeast prion [PSI(+)] provides an epigenetic mechanism for the inheritance of new phenotypes through self-perpetuating changes in protein conformation. [PSI(+)] is a nonfunctional, ordered aggregate of the translation termination factor Sup35p that influences new Sup35 proteins to adopt the same state. The N-terminal region of Sup35p plays a central role in prion induction and propagation. The C-terminal region provides translation termination activity. The function of the highly charged, conformationally flexible middle region (M) is unknown. An M deletion mutant was capable of existing in either the prion or the nonprion state, but in either case it was mostly insoluble. Substituting a charged synthetic polypeptide for M restored solubility, but the prions formed by this variant were mitotically very unstable. Substituting charged flexible regions from two other proteins for M created variants that acquired prion states (defined as self-perpetuating changes in function transferred to them from wild-type [PSI(+)] elements), but had profoundly different properties. One was soluble in both the prion and the nonprion form, mitotically stable but meiotically unstable, and cured by guanidine HCl but not by alterations in heat shock protein 104 (Hsp104p). The other could only maintain the prion state in the presence of wild-type protein, producing Mendelian segregation patterns. The unique character of these M variants, all carrying the same N-terminal prion-determining region, demonstrate the importance of M for [PSI(+)] and suggest that a much wider range of epigenetic phenomena might be based on self-perpetuating, prion-like changes in protein conformation than suggested by our current methods for defining prion states.

Base Sequence↗
PubMed1977

Epigenetic variation of cultured somatic cells: evidence for gradual changes in the requirement for factors promoting cell division.

Cells of higher plant species in culture sometimes lose their requirement for an exogenous supply of a cell division factor that, thereafter, they are able to produce. This heritable change, known as cytokinin habituation, appears to be an epigenetic one rather than a classical mutation because it is directed, potentially reversible, leaves the cell totipotent, and involves the expression of a latent differentiated function. By using cloned cell lines derived from pith parenchyma of tobacco, we have obtained evidence that the habituation process is gradual rather than all-or-none and leads to progressively more autotrophic tissues. Cells in culture show reversible shifts among a range of habituated states but remain totipotent and can be induced to regain their requirement for a cell division factor. Thus, it appears that habituation involves epigenetic changes in a quantitative cellular phenotype. Our findings support the hypothesis that tumor progression in crown gall, a neoplastic disease of higher plants, can be accounted for by heritable changes in the pattern of gene expression.

Cell Differentiation↗
PubMed1998

Release of epigenetic gene silencing by trans-acting mutations in Arabidopsis.

Gene silencing in plants inactivates trans-genes introduced into plants and/or endogenous homologous genes. This stable but potentially reversible loss of gene activity resembles epigenetic changes that occur in normal development. The stability of silencing implies the involvement of trans-acting components, although none of them have been identified so far. Here we report the finding of second-site mutations interfering with maintenance of the silent state. We mutagenized Arabidopsis thaliana plants carrying a silent transgene encoding hygromycin phosphotransferase (hpt) and therefore show a heritable hygromycin-sensitive phenotype. The M2 generation was screened for hygromycin resistance. Eight putative mutants (som1 to 8) were found that expressed the transgene and transmitted the expressed state to their progeny. All mutations were shown to reactivate a silent transgenic test locus in trans. The level of DNA methylation at the hpt locus and at centromeric repeats was found to be reduced in the som mutants. Complementation crosses indicated complex epigenetic interactions among the som mutant alleles and with the previously described ddm1 allele, which elicits DNA hypomethylation [Vongs, A., Kakutani, T, Martiensen, R.A. & Richards, E.J. (1993) Science 260, 1926-1928]. Som mutants can be classified into three groups: (i) allelic or interacting with ddm1 and with each other (som 1,4, and 5), (ii) nonallelic with ddm1 and som mutants of group A (som2), and (iii) mutants with slow resilencing after out-crosses, which hinders their classification (som 3, 6, 7 and 8).

Arabidopsis↗
PubMed1995

Epigenetic gene inactivation induced by a cis-acting methylation center.

In this report we test the hypothesis that a cis-acting methylation center can induce epigenetic gene inactivation. The cis-acting element used is an 838-base pair fragment that was shown previously to provide a de novo methylation signal (Mummaneni, P., Bishop, P. L., and Turker, M.S. (1993) J. Biol. Chem. 268, 552-558). Its normal location is approximately 1.3 kilobase pairs upstream of the mouse aprt (adenine phosphoribosyltransferase) gene. To determine if the methylation center could induce inactivation of the aprt gene, a plasmid construct was created in which the methylation center was moved next to the aprt promoter. Transfection experiments demonstrated inactivation of the aprt gene on the hybrid construct. The inactivation event was shown with a Southern blot analysis to correlate with hypermethylation and to be reversible by treatment with 2-deoxy-5'-azacytidine, a demethylating agent. Interestingly, gene inactivation induced by the methylation center required truncation of the aprt promoter. The results demonstrate that epigenetic gene inactivation can be induced by a DNA methylation center.

Adenine Phosphoribosyltransferase↗
PubMed2002

Epigenetic regulation of a novel tumor suppressor gene (hDAB2IP) in prostate cancer cell lines.

hDAB2IP (human DAB2 (also known as DOC-2) interactive protein) is a novel GTPase-activating protein for modulating the Ras-mediated signal pathway. We demonstrate that the down-regulation of hDAB2IP mRNA in prostate cancer (PCa) cells is regulated by transcriptional levels. Analysis of the hDAB2IP promoter revealed that it is a typical TATA-less promoter containing many GC-rich sequences. In this study, we delineated the potential impact of the epigenetic control of the hDAB2IP promoter on its gene regulation in PCa. Acetylhistone H3 was associated with the hDAB2IP promoter, and CpG islands remained almost unmethylated in normal prostatic epithelia, but not in PCa cell lines. Our data further indicated that trichostatin A (histone deacetylase inhibitor) and 5'-aza-2'-deoxycytidine (DNA hypomethylation agent) acted cooperatively in modulating hDAB2IP gene expression in PCa, whereas histone acetylation played a more significant role in this event. Moreover, a core promoter sequence from the hDAB2IP gene responsible for these treatments was identified. We therefore conclude that epigenetic regulation plays a potential role in regulating hDAB2IP expression in PCa and that these results also provide a new therapeutic strategy for PCa patients.

Base Sequence↗
PubMed2002

LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer.

LOT1 is a zinc-finger nuclear transcription factor, which possesses anti-proliferative effects and is frequently silenced in ovarian and breast cancer cells. The LOT1 gene is localized at chromosome 6q24-25, a chromosomal region maternally imprinted and linked to growth retardation in several organs and progression of disease states such as transient neonatal diabetes mellitus. Toward understanding the molecular mechanism underlying the loss of LOT1 expression in cancer, we have characterized the genomic structure and analyzed its epigenetic regulation. Genome mapping of LOT1 in comparison with the other splice variants, namely ZAC1 and PLAGL1, revealed that its mRNA ( approximately 4.7 kb; GenBank accession number U76261) is potentially spliced using six exons spanning at least 70 kb of the human genome. 5'-RACE (rapid amplification of cDNA ends) data indicate the presence of at least two transcription start sites. We found that in vitro methylation of the LOT1 promoter causes a significant loss in its ability to drive luciferase transcription. To determine the nature of in vivo methylation of LOT1, we used bisulfite-sequencing strategies on genomic DNA. We show that in the ovarian and breast cancer cell lines and/or tumors the 5'-CpG island of LOT1 is a differentially methylated region. In these cell lines the ratio of methylated to unmethylated CpG dinucleotides in this region ranged from 31 to 99% and the ovarian tumors have relatively higher cytosine methylation than normal tissues. Furthermore, we show that trichostatin A, a specific inhibitor of histone deacetylase, relieves transcriptional silencing of LOT1 mRNA in malignantly transformed cells. It appears that, unlike DNA methylation, histone deacetylation does not target the promoter, and rather it is indirect and may be elicited by a mechanism upstream of the LOT1 regulatory pathway. Taken together, the data suggest that expression of LOT1 is under the control of two epigenetic modifications and that, in the absence of loss of heterozygosity, the biallelic (two-hit) or maximal silencing of LOT1 requires both processes.

Alternative Splicing↗
PubMed2004

Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming.

DNA deaminases of the Aid/Apobec family convert cytosine into uracil and play key roles in acquired and innate immunity. The epigenetic modification by methylation of cytosine in CpG dinucleotides is also mutagenic, but this is thought to occur by spontaneous deamination. Here we show that Aid and Apobec1 are 5-methylcytosine deaminases resulting in a thymine base opposite a guanine. Their action can thus lead to C --> T transition mutations in methylated DNA, or in conjunction with repair of the T:G mismatch, to demethylation. The Aid and Apobec1 genes are located in a cluster of pluripotency genes including Nanog and Stella and are co-expressed with these genes in oocytes, embryonic germ cells, and embryonic stem cells. These results suggest that Aid and perhaps some of its family members may have roles in epigenetic reprogramming and cell plasticity. Transition in CpG dinucleotides is the most frequent mutation in human genetic diseases, and sequence context analysis of CpG transitions in the APC tumor suppressor gene suggests that DNA deaminases may play a significant role in tumor etiology.

APOBEC-1 Deaminase↗
PubMed2005

Ochratoxin A: potential epigenetic mechanisms of toxicity and carcinogenicity.

Assessment of the significance to human health of ochratoxin A (OTA) in food is limited by a lack of human toxicity data. Therefore, OTA risk evaluation relies mainly on the use of animal data, with renal carcinogenicity in rat being considered as the pivotal effect. The elucidation of the mechanism of action would improve the use of the carcinogenicity data for risk assessment. Direct genotoxicity versus epigenetic mechanisms appears to be a key question. In this presentation, new biochemical and toxicogenomic results obtained in a recent European project (EU-Grant # QLK1-CT-2001-011614) will be summarized in the context of previously reported mechanisms of action including inhibition of protein synthesis, production of oxidative stress and alteration of cell signalling. Amongst others, the new data indicate that chronic administration of a carcinogenic dose of OTA affected cell-signalling pathways resulting in a significantly reduced renal antioxidant defence and increased oxidative DNA damage. These data confirm previous hypotheses involving oxidative stress as a possible key epigenetic mechanism of OTA toxicity and carcinogenicity.

Animals↗
PubMed2002

Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects.

Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P=.002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P=.012 and P=.02, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P=.003), cancer (P=.03), and hypoglycemia (P=.05). These results define an epigenotype-phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects.

Abdomen↗
PubMed2002

Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19.

Recent data in humans and animals suggest that assisted reproductive technology (ART) might affect the epigenetics of early embryogenesis and might cause birth defects. We report the first evidence, to our knowledge, that ART is associated with a human overgrowth syndrome-namely, Beckwith-Wiedemann syndrome (BWS). In a prospective study, the prevalence of ART was 4.6% (3 of 65), versus the background rate of 0.8% in the United States. A total of seven children with BWS were born after ART-five of whom were conceived after intracytoplasmic sperm injection. Molecular studies of six of the children indicate that five of the six have specific epigenetic alterations associated with BWS-four at LIT1 and one at both LIT1 and H19. We discuss the implications of our finding that ART is associated with human overgrowth, similar to the large offspring syndrome reported in ruminants.

Adult↗
PubMed2006

Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies.

Epigenetic regulation of gene expression is a source of genetic variation, which can mimic recessive mutations by creating transcriptional haploinsufficiency. Germline epimutations and genomic imprinting are typical examples, although their existence can be difficult to reveal. Genomic imprinting can be tissue specific, with biallelic expression in some tissues and monoallelic expression in others or with polymorphic expression in the general population. Mutations in the skeletal-muscle ryanodine-receptor gene (RYR1) are associated with malignant hyperthermia susceptibility and the congenital myopathies central core disease and multiminicore disease. RYR1 has never been thought to be affected by epigenetic regulation. However, during the RYR1-mutation analysis of a cohort of patients with recessive core myopathies, we discovered that 6 (55%) of 11 patients had monoallelic RYR1 transcription in skeletal muscle, despite being heterozygous at the genomic level. In families for which parental DNA was available, segregation studies showed that the nonexpressed allele was maternally inherited. Transcription analysis in patients' fibroblasts and lymphoblastoid cell lines indicated biallelic expression, which suggests tissue-specific silencing. Transcription analysis of normal human fetal tissues showed that RYR1 was monoallelically expressed in skeletal and smooth muscles, brain, and eye in 10% of cases. In contrast, 25 normal adult human skeletal-muscle samples displayed only biallelic expression. Finally, the administration of the DNA methyltransferase inhibitor 5-aza-deoxycytidine to cultured patient skeletal-muscle myoblasts reactivated the transcription of the silenced allele, which suggests hypermethylation as a mechanism for RYR1 silencing. Our data indicate that RYR1 undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing and that this unveils recessive mutations in patients with core myopathies. Furthermore, our data suggest that imprinting is a likely mechanism for this phenomenon and that similar mechanisms could play a role in human phenotypic heterogeneity.

Alleles↗
PubMed2006

Epigenetic regulators and histone modification.

Epigenetic inheritance is a key element in the adaptation of organisms to a rapidly changing environment without stably changing their DNA sequence. The necessary changes in its gene expression profiles are frequently associated with variations in chromatin structure. The conformation of chromatin is profoundly influenced by the post-translational modification of the histone proteins, the incorporation of histone variants, the activity of nucleosome remodelling factors and the association of non-histone chromatin proteins. Although the hierarchy of these factors is still not fully understood, genetic experiments suggest that histone-modifying enzymes play a major causal role in setting up a particular chromatin structure. In this article, the recent progress that was made to understand the molecular mechanisms of the targeting and regulation of histone modifiers and its implication for epigenetic inheritance are reviewed.

Animals↗
PubMed2026

CpGene: a web application for epigenetic signature identification from DNA methylation arrays.

MOTIVATION: DNA methylation (DNAme) is the best studied epigenetic mechanism that plays pivotal role in tissue differentiation and epigenetic disruption has been correlated to diverse disease types (e.g. cancer, metabolic disorders). While various DNAme array platforms have been discovered, data analysis remains a challenging task which often requires in-depth bioinformatic expertise. Here, we developed a user-friendly web-based application for data analysis and visualization that accommodates users ranging from early-career basic/translational researchers to experienced bioinformaticians. RESULTS: CpGene is a web application for analyzing DNA methylation array data. It supports Illumina 450K, EPIC, and EPICv2 methylation array platforms and processes .idat files with integrated preprocessing, normalization, and quality control. Biomarker discovery is available through either classic differential methylation point analysis or machine learning-based feature selection as well as gene enrichment analysis. Results are summarized with clear visualizations, to aid interpretation. By combining these functions in a unified interface, CpGene streamlines methylation analysis and helps identify CpG sites and genes with biological and clinical relevance. AVAILABILITY AND IMPLEMENTATION: CpGene is openly accessible as a web service through http://cpgene.duckdns.org:8001/ and it's source code is available on https://github.com/kostaslazaros/cpgenene.

DNA Methylation↗
PubMed1982

Epigenetic membrane effects of a possible tumor promoting type on cultured liver cells by the non-genotoxic organochlorine pesticides chlordane and heptachlor.

The organochlorine pesticides chlordane and heptachlor were evaluated for their genotoxicity and epigenetic membrane effects. Both compounds were non-genotoxic in the ARLHGPRT mutagenesis assay in which the genotoxic carcinogens 7, 12-dimethylbenz[a]anthracene and benzo[a]pyrene induced significant increases in mutant incidence. The pesticides both markedly inhibited intercellular communication between cultured liver cells, a property demonstrated by many tumor promoting agents, whereas benzo[a]pyrene did not produce this epigenetic effect.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

Epigenetic silencing of E- and N-cadherins in the stroma of mouse thymic lymphomas.

Aberrant expression of some tumour suppressor genes and oncogenes by thymocytes had been involved in the development of primary thymic lymphomas induced by gamma-irradiation, but genetic alterations affecting critical genes expressed by stromal cells have not been yet explored. This paper analyzes a series of such tumours induced in C57BL/6J and in F1 hybrids of BALB/c and C57BL/6J mouse strains. As expected, hystopathological analyses revealed profound disorganizations within the thymus with a poor demarcation of the cortical and medullar areas. Immunological and quantitative on-line RT-PCR analyses confirm that E-cadherin (Cdh1) is essentially expressed by stromal cells of the thymus, while evidencing that the expression of this gene is significantly reduced in all tumours. In addition, and contrary to what one would expect, N-cadherin (Cdh2) that is exclusively expressed by stromal cells is likewise down-regulated in most of the thymic lymphomas. Although hypermethylation of the promoter region appears to be involved in the inactivation of Cdh2 in all tumours, additional epigenetic mechanisms mediated by repressors such as Snai1 may also play a role in Cdh1 silencing. These results represent the first reported case for tumour-associated gene alterations occurring not in the tumour cells per se, but in the stromal cells of primary thymic lymphomas. Additionally, since the expression of both genes is significantly up-regulated after a single high dose of gamma-radiation, but remained unchanged in treated thymic-lymphoma-free-mice, epigenetic down-regulation of E- and N-cadherin appears to occur concomitantly with the progression towards the most advanced stages of gamma-radiation-induced thymic lymphomas.

Animals↗
PubMed2006

Epigenetic alterations in RASSF1A in human aberrant crypt foci.

CpG island methylation (CIM) is an epigenetic mechanism for transcriptional silencing that occurs at various stages of colon tumorigenesis. CIM has been found in serrated adenomas and hyperplastic polyps. There is also evidence for hypermethylation in aberrant crypt foci (ACF) that are found in resected colons from cancer patients. Our study addresses promoter methylation of a tumor suppressor gene, RASSF1A, within the colonic epithelium of subjects undergoing screening colonoscopies in the absence of synchronous tumors. Patients included in this study were at elevated risk for colorectal cancer (CRC) based on family history, but without a previously occurring or synchronous colon carcinoma. ACF were identified using close-focus magnifying chromendoscopy and collected by biopsy in situ. We isolated ACF and adjacent normal colonic epithelium by laser capture microdissection (LCM) and studied methylation of the RASSF1A promoter region in ACF and in adjacent normal mucosa. Expression of RASSF1A was verified using quantitative real-time polymerase chain reaction (QRT-PCR). We found that 8.6% (3 out of 35) of ACF had K-ras mutations and 24% (6 out of 25) had RASSF1A hypermethylation. Our results demonstrate that RASSF1A hypermethylation and K-ras mutations are not mutually exclusive and are present in patients at elevated risk of CRC. Importantly, CIM of RASSF1A is an early epigenetic aberration, occurring in the absence of synchronous colon tumors and is not accompanied by field effects into the surrounding epithelium.

Aged↗
PubMed2006

Discovery of novel epigenetic markers in non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) is a group of malignancies with heterogeneous genetic and epigenetic alterations. Discovery of molecular markers that better define NHL should improve diagnosis, prognosis and understanding of the biology. We developed a CpG island DNA microarray for discovery of aberrant methylation targets in cancer, and now apply this method to examine NHL cell lines and primary tumors. This methylation profiling revealed differential patterns in six cell lines originating from different subtypes of NHL. We identified 30 hypermethylated genes in these cell lines and independently confirmed 10 of them. Methylation of 6 of these genes was then further examined in 75 primary NHL specimens composed of four subtypes representing different stages of maturation. Each gene (DLC-1, PCDHGB7, CYP27B1, EFNA5, CCND1 and RARbeta2) was frequently hypermethylated in these NHLs (87, 78, 61, 53, 40 and 38%, respectively), but not in benign follicular hyperplasia. Although some genes such as DLC-1 and PCDHGB7 were methylated in the vast majority of NHLs, others were differentially methylated in specific subtypes. The methylation of the candidate tumor suppressor gene DLC-1 was detected in a high proportion of primary tumor and plasma DNA samples by using quantitative methylation-specific PCR analysis. This promoter hypermethylation inversely correlated with DLC-1 gene expression in primary NHL samples. Thus, this CpG island microarray is a powerful discovery tool to identify novel methylated genes for further studies of their relevant molecular pathways in NHLs and identification of potential epigenetic biomarkers of disease.

Adult↗
PubMed2006

Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers.

Morphologically, early colorectal tumors are divided into two groups, protruded-type tumors and flat-type tumors. Although some studies have shown genetic alterations in protruded-type tumors, little is known about genetic and epigenetic alterations in flat-type tumors, as well as pT1 (early invasive) colorectal cancers (CRCs). In the current study, we compared the frequencies of genetic and epigenetic alterations of the RAS-RAF and Wnt signaling pathways in flat-type and protruded-type tumors. In addition, we investigated the relationship between those alterations and invasive potential of pT1 CRCs. Methylations of RASSF2, O-6-methylguanine-DNA methyltransferase (MGMT), Wnt inhibitory factor-1 (WIF-1), EPHB2, CDKN2A and MLH1 were detected in 44.3, 30.3, 81.4, 7.5, 43.6 and 13.4% of the 307 early colorectal tumors, respectively. Mutations of KRAS, BRAF, catalytic subunit alpha of phosphatidylinositol 3'-kinase (PIK3CA) and beta-catenin were detected in 25.4, 4.6, 1.6 and 9.4% of those tumors, respectively. Methylations of MGMT, WIF-1 and CDKN2A were detected in significantly higher percentages of protruded-type tumors than in flat-type tumors. Mutation of at least one gene was detected in a significantly higher percentage of flat-type tumors than in protruded-type tumors. RASSF2 methylation was correlated significantly with KRAS, BRAF or PIK3CA mutation. Multiple logistic analysis showed that lymphatic invasion and RASSF2 methylation with KRAS, BRAF or PIK3CA mutation were independent risk factors for venous invasion in pT1 CRCs. In conclusion, since genetic alterations of these pathways have frequently occurred in flat-type tumors, flat-type tumors seem to have a distinct genetic profile different from that of protruded-type tumors. RASSF2 methylation with oncogenic activation is a promising biomarker for predicting invasive potential of pT1 CRCs.

Aged↗