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PubMed2001

Epigenetic silencing of PEG3 gene expression in human glioma cell lines.

Genomic imprinting, the phenomenon in which alleles of genes are expressed differentially depending on their parental origins, has important consequences for mammalian development, and disturbance of normal imprinting leads to abnormal embryogenesis and some inherited diseases and is also associated with various cancers. In the context of screening for novel imprinted genes on human chromosome 19q13.4 with mouse A9 hybrids, we identified a maternal allele-specific methylated CpG island in exon 1 of paternally expressed imprinted gene 3 (PEG3), a gene that exhibits paternal allele-specific expression. Because PEG3 expression is downregulated in some gliomas and glioma cell lines, despite high-level expression in normal brain tissues, we investigated whether the loss of PEG3 expression is related to epigenetic modifications involving DNA methylation. We found monoallelic expression of PEG3 in all normal brain tissues examined and five of nine glioma cell lines that had both unmethylated and methylated alleles; the remaining four glioma cell lines exhibited gain of imprinting with hypermethylated alleles. In addition, treatment of glioma cell lines with the DNA demethylating agent 5-aza-2'-deoxycytidine reversed the silencing of PEG3 biallelically. In this article, we report that the epigenetic silencing of PEG3 expression in glioma cell lines depends on aberrant DNA methylation of an exonic CpG island, suggesting that PEG3 contributes to glioma carcinogenesis in certain cases.

Animals↗

PubMed2004

Epigenetic and gene expression changes related to transgenerational carcinogenesis.

Transgenerational carcinogenesis refers to transmission of cancer risk to the untreated progeny of parents exposed to carcinogens before mating. Accumulated evidence suggests that the mechanism of this process is epigenetic, and might involve hormonal and gene expression changes in offspring. To begin to test this hypothesis, we utilized a mouse model (NIH Swiss) in which exposure of fathers to Cr(III) chloride 2 wk before mating can alter incidence of neoplastic and nonneoplastic changes in offspring tissues. Utilizing a MS-RDA approach, we found that the sperm of these fathers had a significantly higher percentage of undermethylated copies of the 45S ribosomal RNA gene (rRNA); this finding was confirmed by bisulfite sequencing. Because gene methylation is a known mechanism of expression control in germ cells, and ribosomal RNA levels have been linked to cancer, these findings are consistent with the hypothesis. Secondly, we observed that offspring of Cr(III)-treated fathers were significantly heavier than controls, and had higher levels of serum T3. Possible effects of T3 levels on gene expression in the offspring were examined by microarray analysis of cDNAs from liver. A total of 58 genes, including 25 named genes, had expression ratios that correlated significantly with serum T3 ratios at P </= 0.001. Some of these genes have potential roles in growth and/or tumor suppression. These results also support the hypothesis of an epigenetic and/or gene expression-based mechanism for transgenerational carcinogenesis. Published 2004 Wiley-Liss, Inc.

Animals↗

PubMed1990

Assembly of the cricket cercal sensory system: genetic and epigenetic control.

The cercal sensory system of the cricket is being examined using anatomical, physiological, and computer simulation techniques in order to better understand the assembly of sensory systems. This particular sensory system is of interest because it functions like numerically more complex vertebrate sensory systems but offers, to the neuroscientist, the technical advantages of a small number of large identified neurons. Two aspects of sensory processing are being examined in this system; the spatial aspects of a stimulus that tell an animal where a target is in its environment, and the qualities of a stimulus that help the animal to identify the stimulus. The spatial aspects of a stimulus are analyzed by a topographic mapping of the animal's sensory environment. The feature extraction machinery for other aspects of the stimulus lacks any obvious anatomical order and is embedded within the topographic map. We are attempting to tease apart the genetic and the epigenetic components of the assembly process for this sensory system. Here we review our progress with emphasis on the epigenetic aspects of its assembly. We describe previously published work on plasticity as well as new experiments focussed on the role of neuronal activity in the assembly of this neural circuit. Finally, we briefly describe simulation experiments that are helping us understand the role of various forms of synaptic plasticity in the determination of receptive fields.

Animals↗

PubMed2002

Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours.

Cancer is an epigenetic disease at the same level that it can be considered a genetic disease. In fact, epigenetic changes, particularly DNA methylation, are susceptible to change and are excellent candidates to explain how certain environmental factors may increase the risk of cancer. The delicate organization of methylation and chromatin states that regulates the normal cellular homeostasis of gene expression patterns becomes unrecognizable in the cancer cell. The genome of the transformed cell undergoes simultaneously a global genomic hypomethylation and a dense hypermethylation of the CpG islands associated with gene regulatory regions. These dramatic changes may lead to chromosomal instability, activation of endogenous parasitic sequences, loss of imprinting, illegitimate expression, aneuploidy, and mutations, and may contribute to the transcriptional silencing of tumour suppressor genes. The hypermethylation-associated inactivation affects virtually all of the pathways in the cellular network, such as DNA repair (hMLH1, BRCA1, MGMT, em leader), the cell cycle (p16(INK4a), p14(ARF), p15(INK4b), ...), and apoptosis (DAPK, APAF-1, ...). The aberrant CpG island methylation can also be used as a biomarker of malignant cells and as a predictor of their behaviour, and may constitute a good target for future therapies.

Chromatin↗

PubMed2006

Lack of genetic and epigenetic changes in meningiomas without NF2 loss.

Approximately 60% of sporadic meningiomas are caused by inactivation of the NF2 tumour suppressor gene. The causative gene for the remaining meningiomas is unknown. Previous studies have shown that these tumours have no recurrent karyotypic abnormalities. They differ from their NF2-related counterparts in that they are more often of the meningothelial subtype and are located preferentially in the anterior skull base. To gain more insight into the aetiology of these tumours, we studied genetic and epigenetic alterations in 25 meningiomas without NF2 involvement. We first established a genome-wide allelotype using 3 microsatellite markers per chromosome arm. Loss of heterozygosity (LOH) was detected at a low frequency and no indication for the location of putative tumour suppressor genes could be established. We next screened the subtelomeric regions by using 2-3 polymorphic markers close to each telomere. Again no evidence for LOH of a particular chromosome arm was obtained, and no LOH was found in the genomic regions containing the NF2-related ERM family members ezrin and radixin, DAL-1, protein 4.1R, and TSLC1. Mutations in the X-chromosome based family member, moesin, were analysed by SSCP and were not detected. Microsatellite instability was studied using 6 commonly used markers but none of these was altered in any meningioma. Methylation was detected in 5 of 16 genes (NF2, p14(ARF), CDH1, BRCA1, RB1) previously shown to be silenced in a variety of tumour types. However, methylation percentages for these genes were generally higher in a group of NF2-related meningiomas, with the exception of the BRCA1 gene. The NF2 gene was methylated in only 1 of 21 tumours. In conclusion, meningiomas with an intact NF2 gene have a normal karyotype and no obvious genetic or epigenetic aberrations, suggesting that the gene(s) involved in the pathogenesis of these tumours are altered by smaller events than can be detected with the techniques used in our study.

Adult↗

PubMed2026

Epigenetic Reprogramming and Zygotic Genome Activation in Human Preimplantation Development: Mechanisms, Models, and Translational Prospects.

PURPOSE: Early human embryogenesis unfolds through a tightly coupled sequence of events-clearance of maternal transcripts, remodeling of parental chromatin, zygotic genome activation (ZGA), lineage segregation, implantation, and post-implantation patterning-accompanied by epigenetic reprogramming, including X-chromosome dosage compensation around the time of implantation. This review aims to synthesize recent advances in understanding this developmental program and to consider their implications for reproductive medicine. METHODS: I review recent literature on human early embryogenesis, with particular emphasis on findings enabled by single-cell genomics and stem-cell-based embryo modeling, and integrate these insights to identify human-specific features of early development. RESULTS: These approaches have made previously inaccessible aspects of human early embryogenesis experimentally tractable, revealing molecular and epigenetic features that distinguish human development from that of model organisms, including species-specific dynamics of ZGA, maternal transcript clearance, chromatin reprogramming, and X-chromosome dosage compensation. CONCLUSIONS: Advances in single-cell genomics and embryo modeling are transforming our understanding of human early embryogenesis. Building on these insights, while recognizing their current limitations, I propose a vision for improving reproductive medicine, including the potential for next-generation embryo selection strategies.

Journal Article↗

PubMed1999

Epigenetic regulation of gelsolin expression in human breast cancer cells.

Gelsolin is a multifunctional, actin-binding protein that is greatly decreased in many transformed cell lines and tumor tissues, including breast cancers. Downregulation of gelsolin RNA occurs in most breast cancers of rats, mice, and humans, but gross mutations of the gelsolin gene have not been found. Here we demonstrate by PCR and RT-PCR analysis that there are no point mutations in putative regulatory regions or the entire coding region of the cytoplasmic isoform of the gelsolin gene in human breast cancer cells (BCC). To determine if epigenetic modification is involved in downregulating gelsolin expression in MDA-MB-231 (MDA231), MCF7, and T47D BCC, we have used Southern blot analysis, 5-azacytidine (5aza) treatment, and trichostatin A (TSA) treatment. Southern blot analysis performed on genomic DNA demonstrated altered CpG methylation within intron 1 in DNA from all BCC compared to normal, mortal human mammary epithelial cells (HMEC). Treatment of the BCC with 5aza converted the DNA restriction pattern to that seen in untreated HMEC genomic DNA and caused modest increases in gelsolin RNA and protein. Incubation with TSA, an inhibitor of histone deacetylase, induced a dramatic upregulation of gelsolin RNA and protein levels which preceded apoptotic death of all BCC within 48-60 h. Our data support a role for epigenetic changes in chromatin structure leading to downregulation of gelsolin expression in human breast cancer. To our knowledge, this is the first example of a tumor suppressor gene downregulated in human breast cancer by changes in histone acetylation.

Acetylation↗

PubMed1995

Fixation of epigenetic states in a population.

Multiple steady-state levels of autoregulatory transcription factors constitute alternative epigenetic states, and could help specify the heritable phenotype of an organism. In this work, the inheritance of autoregulatory transcription factors through sexual reproduction is modeled to determine the conditions under which different alternative epigenetic states become fixed in a population. The influence of transient environmental perturbations on the fixation of states is discussed in the context of speciation.

Animals↗

PubMedDate not supplied

Genetic and epigenetic regulation schemes: need for an alternative paradigm.

Self-organization of living cells results from the tangle of positive and negative feedback developed to ensure their homeostasis and/or their differentiation. There are three major means cellular regulation operates: the genetic, the epigenetic, and the metabolic ones. The regulation type in each of them has been overviewed. Further examination of relations between complexity and developmental stability points out sui generis properties of feedback loops, which are redundancy and pleiotropy. Prototypical schemes for positive and negative regulation with redundant and pleiotropic (including multifunctional) proteins are presented. They stress a theoretical shift from the analytical to the systemic framework. The systemic paradigm appears to be of increasing interest and importance in the study of concepts for the representation of genetic and epigenetic regulations.

Animals↗

PubMed1993

Epigenetic repeat-induced gene silencing (RIGS) in Arabidopsis.

In several plant systems expression of structurally intact genes may be silenced epigenetically when a transgenic construct increases the copy number of DNA sequences. Here we report epigenetic silencing in Arabidopsis lines containing transgenic inserts of defined genetic structure, all at the same genomic locus. These comprise an allelic series that includes a single copy of the primary insert, which carries repeated drug resistance transgenes, and a set of its derivatives, which as a result of recombination within the insert carry different numbers and alleles of resistance genes. Although the drug resistance genes remained intact, both the primary and some recombinant lines nevertheless segregated many progeny that were partly or fully drug-sensitive because of silencing. As in other systems silencing was reversible, and correlated with decreased steady-state mRNA and increased DNA methylation. Each different number and combination of genes, on the same or different (i.e., homologous) chromosomes, conditioned its own idiosyncratic segregation pattern. Strikingly, lines with a single gene segregated only a few slightly drug-sensitive progeny whereas multi-gene lines segregated many highly sensitive progeny, indicating dependence of silencing at this locus on repeated sequences. This argues strongly against explanations based on antisense RNA, but is consistent with explanations based on ectopic DNA pairing. One possibility is that silencing reflects the interaction of paired homologous DNA with flanking heterologous DNA, which induces condensation of chromatin into a non-transcribable state.

Arabidopsis↗

PubMed1994

Epigenetic variants of a transgenic petunia line show hypermethylation in transgene DNA: an indication for specific recognition of foreign DNA in transgenic plants.

We analysed de novo DNA methylation occurring in plants obtained from the transgenic petunia line R101-17. This line contains one copy of the maize A1 gene that leads to the production of brick-red pelargonidin pigment in the flowers. Due to its integration into an unmethylated genomic region the A1 transgene is hypomethylated and transcriptionally active. Several epigenetic variants of line 17 were selected that exhibit characteristic and somatically stable pigmentation patterns, displaying fully coloured, marbled or colourless flowers. Analysis of the DNA methylation patterns revealed that the decrease in pigmentation among the epigenetic variants was correlated with an increase in methylation, specifically of the transgene DNA. No change in methylation of the hypomethylated integration region could be detected. A similar increase in methylation, specifically in the transgene region, was also observed among progeny of R101-17del, a deletion derivative of R101-17 that no longer produces pelargonidin pigments due to a deletion in the A1 coding region. Again de novo methylation is specifically directed to the transgene, while the hypomethylated character of neighbouring regions is not affected. Possible mechanisms for transgene-specific methylation and its consequences for long-term use of transgenic material are discussed.

Chromatin↗

PubMed1986

Simultaneous induction of epigenetic variants.

Epigenetic changes at one, two, or three loci were induced with 5-azacytidine in CHO-K1 cells, using markers (proline dependence, asparagine dependence, and thymidine kinase deficiency) which respond by high-frequency reversion to wild-type states. The observed incidence of dual or triple revertants was compared with the frequency expected by chance as the product of single frequencies measured separately for the markers involved. Values observed for dual reversions consistently exceeded levels predicted by this purely stochastic model, and for triple reversion the divergence was 1000-fold. Coordinate responses could account for this disparity, if minority cell types with higher reactivity to 5-azacytidine exist in target cell populations. To test this hypothesis, single colonies were isolated under nonselective conditions from a mass culture of CHO-K1 cells that had been treated with 5-azacytidine. These clones showed wide and reproducible differences in competence for reversion from proline dependence to independence. Our data thus suggest that simultaneity of epigenetic changes depends on random events which are modulated by a mosaic of inductive potentials within individual cells of the reacting system.

Animals↗

PubMed2002

Epigenetics of dominance for enzyme activity.

We have isolated and purified two parental homodimers and a unique heterodimer of acid phosphatase [coded by Acph-1 (1.05)(F) and Acph-1 (0.95)(S)] from isogenic homozygotes and heterozygotes of Drosophila malerkotliana. F and S produce qualitatively different allozymes and the two alleles are expressed equally within and across all three genotypes and F and S play an equal role in the epigenetics of dominance. Subunit interaction in the heterodimer over a wide range of H+ concentrations accounts for the epigenetics of dominance for enzyme activity.

Acid Phosphatase↗

PubMedDate not supplied

DNA methylation and epigenetic mechanisms.

Genes are essential for the transmission of genetic information from generation to generation, and this mechanism of inheritance is fully understood. Genes are also essential for unfolding the genetic program for development, but the rules governing this process are obscure. Epigenetics comprises the study of the switching on and off of genes during development, the segregation of gene activities following somatic cell division, and the stable inheritance of a given spectrum of gene activities in specific cells. Some of these processes may be explained by DNA modification, particularly changes in the pattern of DNA methylation and the heritability of that pattern. There is strong evidence that DNA methylation plays an important role in the control of gene activity in cultured mammalian cells, and the properties of a CHO mutant strain affected in DNA methylation are described. Human diploid cells progressively lose cytosine methylation during serial subculture, and this may be related to their in vitro senescence. There is also evidence that DNA modifications can be inherited through the germ line. Classical genetics is based on the study of all types of change in DNA base sequence, but the rules governing the activity of genes by epigenetic mechanisms are necessarily different. Their elucidation will depend both on a theoretical framework for development and on experimental studies at the molecular, chromosomal, and cellular levels.

Animals↗

PubMed2006

Epigenetic diagnostics of cancer--the application of DNA methylation markers.

In recent years it has become apparent that epigenetic events are potentially equally responsible for cancer initiation and progression as genetic abnormalities. DNA methylation is the main epigenetic modification in humans. Two DNA methylation lesions coexist in human neoplasms: hypermethylation of promoter regions of specific genes within a context of genomic hypomethylation. Aberrant methylation is found at early stages of carcinogenesis and distinct types of cancer exhibit specific patterns of methylation changes. Tumor specific DNA is readily obtainable from different clinical samples and methylation status analysis often permits sensitive disease detection. Methylation markers may also serve for prognostic and predictive purposes as they often reflect the metastatic potential and sensitivity to therapy. As current findings show a great potential of recently characterised methylation markers, more studies in the field are needed in the future. Large clinical studies of newly developed markers are especially needed. The review describes the diagnostic potential of DNA methylation markers.

Biomarkers, Tumor↗

PubMed2004

Epigenetic tinkering and evolution: is there any continuity in the role of cytosine methylation from invertebrates to vertebrates?

The function of DNA methylation has been investigated in depth in vertebrate and plant genomes, establishing that it is involved in gene silencing and transposon control. Data regarding insect methylation, even if still scanty, apparently argue against evolutionary conservation of DNA methylation functions. Cytosine methylation, therefore, proves to be an epigenetic tool repeatedly used to accomplish different functions in different taxa according to a sort of epigenetic tinkering occurring during evolution.

Animals↗

PubMed2003

A test for a metastable epigenetic component of heterosis using haploid induction in maize.

We conducted a test to detect if there is a heritable epigenetic component to hybrid vigor and/or inbreeding depression. The impetus for this work was a classical study of the effect of homozygosis on the expression of the maize red color ( r1) locus. It had been shown that maintaining R1 mottling alleles in the homozygous state over several generations produces a progressive decrease of their paternally imprinted expression. This effect is reversed by R1/r1 allele heterozygosity. If this behavior were characteristic of many regulatory genes, then such a phenomenon could contribute to inbreeding depression and heterosis. To examine this question, inbreds of Mo17 and B73 and the two reciprocally produced hybrids were crossed by Stock 6 to generate four classes of maternal haploids. The mature haploid plants were measured for several quantitative traits. If inbreeding depression results from an accumulating heritable effect that is reversed by the hybrid state, one would expect the haploids derived from the hybrids to perform better than those derived from the inbred lines. The hybrid-derived haploids did not exhibit greater average performance than the inbred-derived haploids. These data fail to support the hypothesis that inbreeding depression and heterosis have a metastable epigenetic component.

Epigenesis, Genetic↗

PubMed2003

Epigenetic silencing may aid evolution by gene duplication.

Gene duplication is commonly regarded as the main evolutionary path toward the gain of a new function. However, even with gene duplication, there is a loss-versus-gain dilemma: most newly born duplicates degrade to pseudogenes, since degenerative mutations are much more frequent than advantageous ones. Thus, something additional seems to be needed to shift the loss versus gain equilibrium toward functional divergence. We suggest that epigenetic silencing of duplicates might play this role in evolution. This study began when we noticed in a previous publication (Lynch M, Conery JS [2000] Science 291:1151-1155) that the frequency of functional young gene duplicates is higher in organisms that have cytosine methylation (H. sapiens, M. musculus, and A. thaliana) than in organisms that do not have methylated genomes (S. cerevisiae, D. melanogaster, and C. elegans). We find that genome data analysis confirms the likelihood of much more efficient functional divergence of gene duplicates in mammals and plants than in yeast, nematode, and fly. We have also extended the classic model of gene duplication, in which newly duplicated genes have exactly the same expression pattern, to the case when they are epigenetically silenced in a tissue- and/or developmental stage-complementary manner. This exposes each of the duplicates to negative selection, thus protecting from "pseudogenization." Our analysis indicates that this kind of silencing (i) enhances evolution of duplicated genes to new functions, particularly in small populations, (ii) is quite consistent with the subfunctionalization model when degenerative but complementary mutations affect different subfunctions of the gene, and (iii) furthermore, may actually cooperate with the DDC (duplication-degeneration-complementation) process.

Animals↗