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Results for “epigenetic modification”

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At least 433 records · Page 24Linked to original sources
PubMed2002

Functional genomics in experimental and human temporal lobe epilepsy: powerful new tools to identify molecular disease mechanisms of hippocampal damage.

The human genome project is a milestone for molecular genetic studies on complex, sporadic disorders in the human central nervous system (CNS). Functional analysis and tissue-/cell-specific expression profiles will be of particular importance anticipating the magnitude of expressed genes in the brain and their dynamic epigenetic modifications. The recent progress in microarray technologies allows expression studies for a large number of genes. In combination with laser-microdissection and quantitative reverse transcription-polymerase chain reaction technologies, such large-scale expression analyses can be successfully addressed in well-defined tissue specimens or cellular subpopulations. Complex, sporadic diseases, such as temporal lobe epilepsy (TLE), are challenging for functional genomics. Issues of particular importance in this field include molecular mechanisms of neurodevelopmental abnormalities, neuronal plasticity and hyperexcitability as well as neuronal cell damage in affected CNS areas. The availability of anatomically well-preserved surgical specimens, i.e. hippocampus obtained from epilepsy patients with Ammon's horn sclerosis or focal lesions not affecting the hippocampus proper as well as comparisons with experimental TLE models may help to elucidate specific molecular-pathological mechanisms during epileptogenesis and in chronic conditions of the disease.

Animals↗
PubMed1996

Genomic imprinting and mammalian development.

Genomic imprinting, which results in the mono-allelic expression of certain genes in a parent of origin-dependent manner, represents a specialized form of gene regulation which may be vitally important for mammalian development. The mechanisms which underlie imprinting and the molecular nature of the imprint itself remain elusive but most likely include epigenetic modifications of DNA, such as methylation and chromatin structure changes. It is clear, however, that many of the known imprinted genes play important developmental roles and that changes in the functional imprinting of some of these genes may have important pathological consequences, including placental abnormalities.

Animals↗
PubMed2003

Teaching cells new tricks.

The direct conversion of one differentiated cell type into another--a process referred to as transdifferentiation--would be beneficial for producing isogenic (patient's own) cells to replace sick or damaged cells or tissue. Adult stem cells display a broader differentiation potential than anticipated and might contribute to tissues other than those in which they reside. As such, they could be worthy therapeutic agents. Recent advances in transdifferentiation involve nuclear transplantation, manipulation of cell culture conditions, induction of ectopic gene expression and uptake of molecules from cellular extracts. These approaches open the doors to new avenues for engineering isogenic replacement cells. To avoid unpredictable tissue transformation, nuclear reprogramming requires controlled and heritable epigenetic modifications. Considerable efforts remain to unravel the molecular processes underlying nuclear reprogramming and evaluate stable of the changes in reprogrammed cells.

Adipocytes↗
PubMed2002

Oogenesis as a foundation for embryogenesis.

The majority of oocytes in postnatal ovaries are small, non-growing and reside in primordial follicles. They have to undergo a prolonged phase of growth and differentiation before nuclear and cytoplasmic maturation enables them to resume meiosis and undergo fertilization. A better knowledge of this phase of oogenesis is essential for understanding causes of oocyte pathology and optimizing methods for growing oocytes in vitro and for cryopreservation. There could also be spin-off discoveries for contraceptive strategies and pharmacologically controlling oocyte maturation. During oocyte growth, a molecular programme for development is assembled for the timely expression of mRNAs, some of which are expressed throughout oogenesis while others are 'masked' until or after meiotic maturation. Masking and stability in storage are largely due to a truncated poly(A) tail, controlled by regulatory sequences on the 3'-untranslated region (UTR) of the mRNA. Most maternal RNAs are degraded early in cleavage, there being a narrow overlap between persisting maternal mRNAs and activation of the embryonic genome. Accumulation of RNAs and proteins are not, however, the only major changes taking place during oogenesis. Cytoplasmic organelles multiply and redistribute, and there are epigenetic modifications of DNA for monoallelic expression of imprinted genes. The granulosa cells are obligatory for they provide physical support, nutrients and mediate the regulatory influences of gonadotrophic hormones. On the other hand, the oocyte actively influences the growth and differentiation of its granulosa cells. Thus, healthy embryos reflect the quality of both the oocyte and the granulosa cells.

Animals↗
PubMed2001

Genomic imprinting and cancer; new paradigms in the genetics of neoplasia.

The role of epigenetic modification of gene expression is becoming increasingly important in how we understand the loss of tumour suppressor gene function in a variety of tumours and tumour predisposing syndromes. This review explores the importance of epimutation in Beckwith-Wiedemann syndrome and Wilms' tumour and focuses on genomic methylation in both imprinted and non-imprinted genes as a key mechanism in the development of cancer.

Aging↗
PubMed2002

Aging of animals produced by somatic cell nuclear transfer.

Cloning by somatic cell nuclear transfer (NT) has been used to successfully generate viable mammalian embryos in many species. Despite the successful production of cloned animals, NT remains an inefficient technique at best. High rates of developmental failure and abnormalities are associated with NT-derived animals. Issues such as cell cycle regulation, epigenetic modification and oocyte activation have been examined in order to ultimately find ways to improve the efficiency of somatic cell NT. In reviewing the available literature regarding the generation of various mammalian species by using somatic cell NT, it becomes apparent that there are not only differences in the protocols used to generate such animals, but significant differences in the phenotypes of resultant animal clones as well. In this review we discuss the current findings about how aging and senescence are affected by somatic cell NT in mammals.

Aging↗
PubMed1999

Commentary on Annett, Yeo et al., Klar, Saugstad and Orr: cerebral asymmetry, language and psychosis--the case for a Homo sapiens-specific sex-linked gene for brain growth.

Annett, Yeo et al. and Klar have each proposed theories that relate the genetics of cerebral lateralization to predisposition to psychosis. These theories are considered in relation to the central paradox that psychosis is associated with a substantial biological disadvantage. Annett's heterozygote advantage hypothesis critically identified lateralization as a major determinant of ability, but it appears that what is inherited is degrees (as suggested by Yeo et al.) rather than (or as well as) direction of lateralization. Relative hand skill has been shown (Crow, T.J., Crow, L.R., Done, D.J., Leask, S.J., 1998. Relative hand skill predicts academic ability: global deficits at the point of hemispheric indecision. Neuropsychologia 36, 1275-1282.) to be a powerful predictor (interacting with sex) of academic ability but the greatest region of vulnerability (that includes reading disability and predisposition to psychosis) is close to the point of equal hand skill ('hemispheric indecision'). In contrast with Annett's single locus, Yeo's polygenic and Klar's strand-segregation hypotheses, each of which postulates an autosomal locus or loci, the hypothesis of a single gene for asymmetry located in a sex-specific region of homology on both X and Y chromosomes can account for sex differences, as observed in age of onset, and premorbid precursors of psychosis, as well as differences in the general population in relation to degrees of hand skill, verbal ability and cerebral asymmetry. The evolutionarily recent transposition to, and subsequent paracentric inversion in, the Y chromosome short arm of a 4-Mb block from Xq21.3 (the proximal long arm of the X) are candidates for speciation events in the lineage that led to Homo sapiens. A gene associated with a range of variation (that may be due to a high mutation site, or perhaps to epigenetic modification) on the Y that overlaps with, but differs quantitatively from, that on the X may explain the sex differences associated with psychosis, and may be relevant to its persistence. Such a gene could be the principal determinant in Man of the rate of brain growth, as suggested by Saugstad and by the findings of a recent study of adolescent onset psychosis (James, A., Crow, T.J., Renowden, S., Wardell, M., Smith, D.M., Anslow, P., in press. Is the course of brain development in schizophrenia delayed? Evidence from onsets in adolescence. Schizophr. Res.).

Biological Evolution↗
PubMed2000

Increased cell proliferation and R.Msp1 fragmentation induced by 5-aza-2'-deoxycytidine in rat testes related to the gene imprinting mechanism.

DNA methylation is one of the crucial mechanisms for cellular and tissue differentiation during developmental stages in mammals. 5-aza-2'-deoxycytidine, a specific cytosine DNA Methyltransferase inhibitor, is known to cause DNA hypomethylation in CpG, CpNpG and CCGG sequences. Therefore the present study was designed to determine the effects of 5-aza-2'-deoxycytidine on the germinal cells of the adult rat testicular tissue. Rat testicular tissues from the 5-aza-2'-deoxycytidine treated experimental and non-treated control groups were processed for light microscopy and also for genomic DNA isolation assays. The isolated genomic DNAs were digested with R.Msp1 in order to determine the methyl pattern differences in the enzyme cognate CCGG sequence. Testicular tissues from treated rats showed increased cell proliferation when investigated at the light microscopical level. On the other hand, genomic DNA of these proliferative tissue showed high fragmentation sizes of R.Msp1 digestion when compared to controls. While the R.Msp1 digested control group DNA fragmentation condensed at approximately 4700-5100 bps size, the experimental group DNA fragmentation was condensed at 700-900 bps size. In addition, 5-aza-2'-deoxycytidine has effects on increased cell proliferation via the loss of somatic de novo gene imprinting. These results imply that abnormally imprinted normal somatic cells in mammals are susceptible to epigenetic modification. These results also suggest that the genomic DNA of testicular tissues from control rats is resistant to R.Msp1 while DNA from the experimental group testicular cells demonstrating high proliferation rate could not resist to R.Msp1 digestion due to DNA hypomethylation in CCGG sequence. In conclusion, it could be suggested that the reversal of gene imprinting in germinal cells may cause an increased cellular proliferation and R.Msp1 fragmentation when induced by 5-aza-2'-deoxycytidine.

Animals↗
PubMed2002

Allelic exclusion at the TCRbeta locus.

Assembly of TCRbeta chain variable-region genes is regulated in the context of allelic exclusion. Differential epigenetic modifications of the two TCRbeta alleles established early in embryonic development may be important for permitting allelic exclusion by ordering rearrangement of the two alleles in double-negative thymocytes. Expression of a TCRbeta chain, as part of the pre-TCR complex, activates signaling pathways that enforce allelic exclusion in double-positive thymocytes. These signaling pathways, which utilize p56(lck) and SLP-76, may be distinct from those used to promote other processes initiated by pre-TCR expression. In double-positive thymocytes allelic exclusion is enforced, in part, by changes in Vbeta gene segment accessibility promoted by cis-acting elements that may be distinct from those regulating accessibility of D/Jbeta gene segments.

Alleles↗
PubMed2001

Epigenetic developmental mechanisms in plants: molecules and targets of plant epigenetic regulation.

Genetic approaches to understanding the role of epigenetic regulation of gene expression in plants and its mechanisms have revealed several new components. Rapidly accumulating information from other eukaryotes provides complementary knowledge with important implications for plant research. Comparison of epigenetic events across species is proving critical for defining the mechanisms and functions of epigenetic modification, including those specific to plants.

Chromatin↗
PubMed1994

Parental imprinting of autosomal mammalian genes.

The molecular mechanisms introducing epigenetic modifications that lead to differential silencing of some autosomal alleles depending on their parental legacy are still largely unknown, but recent results from studies of endogenously imprinted genes and particular transgenes make DNA methylation a strong candidate. At the same time, these results have raised new questions about the details of the imprinting process.

Animals↗
PubMed2002

Interplay between two epigenetic marks. DNA methylation and histone H3 lysine 9 methylation.

BACKGROUND: The heterochromatin of many eukaryotes is marked by both DNA methylation and histone H3 lysine 9 (H3-K9) methylation, though the exact relationship between these epigenetic modifications is unknown. In Neurospora, H3-K9 methylation is required for the maintenance of all known DNA methylation. In Arabidopsis, H3-K9 methylation directs some of the CpNpG and asymmetric methylation. However, it is not known in any organism whether DNA methylation may also direct histone H3 methylation. RESULTS: Using chromatin immunoprecipitation (ChIP) assays, we show that Arabidopsis heterochromatin is associated with H3-K9 methylation. This histone methylation is dependent on the KRYPTONITE and DDM1 genes (SU[VAR]3-9 and SWI2/SNF2 homologs, respectively). We also find that a decrease in DNA methylation does not directly cause a loss of H3-K9 methylation. Instead, a decrease in H3-K9 methylation is only seen at loci where transcription is derepressed. CONCLUSIONS: We conclude that DNA methylation does not control the methylation of histone H3-K9. We propose that loss of H3-K9 methylation is due to transcriptional reactivation, coupled with deposition of unmethylated nucleosomes. These findings are consistent with recent observations of DNA replication-independent deposition of histone H3.3 in Drosophila. Our results also suggest that, in Arabidopsis, DNA methylation is sufficient for gene silencing, but H3-K9 methylation is not.

Arabidopsis↗
PubMed1998

Helper T cell differentiation is controlled by the cell cycle.

Helper T (Th) cell differentiation is highly regulated by cytokines but initiated by mitogens. By examining gene expression in discrete generations of dividing cells, we have delineated the relationship between proliferation and differentiation. Initial expression of IL-2 is cell cycle-independent, whereas effector cytokine expression is cell cycle-dependent. IFNgamma expression increases in frequency with successive cell cycles, while IL-4 expression requires three cell divisions. Cell cycle progression and cytokine signaling act in concert to relieve epigenetic repression and can be supplanted by agents that hyperacetylate histones and demethylate DNA. Terminally differentiated cells exhibit stable epigenetic modification and cell cycle-independent gene expression. These data reveal a novel mechanism governing Th cell fate that initially integrates proliferative and differentiative signals and subsequently maintains stability of the differentiated state.

Animals↗
PubMed1998

Position effects and epigenetic silencing of plant transgenes.

Nuclear processes that silence plant transgenes are being revealed by analyses of natural triggers of epigenetic modifications, particularly cytosine methylation, and by comparisons of the genomic environments of differentially expressed transgene loci. It is increasingly apparent that plant genomes can sense and respond to the presence of foreign DNA in certain sequence contexts and at multiple dispersed sites. Determining the basis of this sensitivity and how nuclear defense systems are activated poses major challenges for the future.

Cytosine↗
PubMed1997

Formation of methylation patterns in the mammalian genome.

Cytosine methylation in mammals is an epigenetic modification required for viability of the developing embryo. It has been suggested that DNA methylation plays important roles in X-chromosome inactivation, imprinting, protection of the genome from invasive DNA sequences, and compartmentalization of the genome into active and condensed regions. Despite the significance of DNA methylation in mammalian cells, the mechanisms used to establish methylation patterns during development are not understood. This review will summarize the current state of knowledge about potential roles for cis- and trans-acting factors in the formation of methylation patterns in the mammalian genome.

Animals↗
PubMed1997

DNA methylation in genomic imprinting.

As a reversible epigenetic modification which can affect gene expression, DNA methylation has been an attractive candidate for the biochemical mechanism of genomic imprinting. Many correlations in mice and humans link allele-specific DNA methylation to the allele-restricted RNA expression which is the hallmark of imprinted genes. Moreover, abnormal DNA methylation accompanies the pathological functional imprinting of certain human genes on chromosome 11p15.5 in Wilms' tumors and in the Beckwith-Weidemann syndrome and on chromosome 15q11-13 in the Prader-Willi and Angelman syndromes. A role for DNA methylation in maintaining the transcriptional silence of imprinted alleles at some loci has been supported by pharmacological manipulation with 5-aza-2'-deoxycytidine and by experiments with methyltransferase deletion mice. Gametic differences in DNA methylation could also account for the initiation of imprints, but this remains unproven. Comprehensive physical models for the role of DNA methylation in imprinting must account not only for local allele-restricted gene expression but also for the existence of large chromosomal domains containing multiple coordinately imprinted genes.

Angelman Syndrome↗
PubMed2002

Epigenetic changes in tumor Fas levels determine immune escape and response to therapy.

Epigenetic regulation of gene expression significantly influences cell growth and differentiation. Here we show that epigenetic silencing of Fas determines tumor growth in vivo and apoptotic sensitivity in vitro. In established tumors with epigenetically repressed Fas, restoration of Fas activity either by transfection of fas or treatment with Trichostatin A (TSA), an inhibitor of histone deacetylase, suppresses tumor growth and restores chemosensitivity. The TSA-dependent chemosensitivity and tumor growth control require both tumor Fas and the host NK (natural killer) cell functions. This work demonstrates the importance of epigenetic modification of Fas in tumor progression and immune evasion, and emphasizes the essential interplay between Fas and innate immunity in the control of chemoresistant tumors.

Animals↗
PubMed1997

Silencing of a beta-1,3-glucanase transgene is overcome during seed formation.

Expression of a beta-1,3-glucanase transgene (gn1) driven by the CaMV 35S promoter is silenced in the T17 homozygous tobacco transgenic line. This silencing process is post-transcriptionally regulated and subject to developmental control. We have examined this phenomenon to investigate the developmental pathways involved in suppression and reactivation of gn1 expression as well as to identify the plant tissues where these processes occur. Analysis of beta-1,3-glucanase activity and gene expression have allowed us to determine that suppression of gn1 is a very efficient process reducing the steady-state gn1 mRNA level, simultaneously, in all leaves of the plant. Gene silencing occurs a few weeks after seed germination, and is maintained throughout vegetative growth and floral development. Expression of gn1 is restored in the maturing fruit some time after fertilization. In situ hybridization analyses show that expression of gn1 is restored within the developing seeds in tissues derived from meiotically divided cells. In contrast to the high level of expression found in seedlings obtained from germinated T17 homozygous seeds, the expression of gn1 is not reactivated in plantlets regenerated in vitro from leaf explants of suppressed T17 homozygous plants that is, in plant tissues obtained by mitotic division. Thus, reactivation of gn1 expression specifically occurs along the developmental programme controlling sexual reproduction and likely throughout epigenetic modifications affecting the state of gene expression during meiosis.

Fruit↗