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At least 955 records · Page 53Linked to original sources
PubMed1998

Insulin-like growth factor II receptor, transforming growth factor-beta, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis.

The B10/B10.A congenic mouse pair serves as a model for identifying specific genes related to morphogenesis and dysmorphogenesis of the embryonic palate and other organs. The present report describes our initial investigation of the Fraser-Juriloff paradigm, which proposes that susceptibility to malformation results from genetically determined differences in normal developmental patterns. Specifically, we evaluated the relationship between Igf2r gene expression, transforming growth factor-beta (TGF-beta) activation, and cdk4 gene expression. By using in situ hybridization, RNase protection assays, indirect immunofluorescence, Western blots, and bioassays, we show 1) the presence of insulin-like growth factor II (IGF-II), IGF-II receptor (IGF-IIR), IGF-IR, TGF-beta, plasminogen, plasminogen activators [urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA)], and Cdk4 in developing palates; 2) on embryonic day 14 (E14), which is a critical day for palatal growth, B10.A embryos have 82% greater IGF-IIR mRNA than B10; 3) on E14, B10.A embryonic palates have a 57% greater level of active TGF-beta2 than B10, although the total TGF-beta2 is nearly identical; and 4) on E14, B10 embryonic palates have a 52% greater level of Cdk4 mRNA than B10.A palates, a measure of cell cycle progression. Because cellular activation of latent TGF-beta appears to require binding to the mannose-6-phosphate (M6P) binding site of the IGF-IIR and is plasmin and plasminogen activator dependent, the positive correlation of IGF-IIR levels and active TGF-beta2 levels seems to be key. Thus, the strain variation of TGF-beta2/IGF-IIR-mediated growth inhibition in late G1 phase would appear to account for the slower growth and development of B10.A palates relative to B10. Elevated corticosteroid (CORT) exposure in E14 B10.A embryos significantly increases TGF-beta levels, 87% of which is TGF-beta2, as well as the levels of active TGF-beta, 64% of which is TGF-beta2. Without exogenous CORT, B10.A embryos do not have clefts; hence, we present an outline of pathogenesis: slower growing B10.A embryos have an up-regulation of IGF-IIR, which serves to sequester IGF-II from the growth-promoting IGF-IR and to bind more CORT-up-regulated, latent TGF-beta2 for subsequent plasmin-dependent activation; higher levels of TGF-beta2 signaling down-regulate Cdk4 and result in greater palatal growth inhibition at a critical stage of palatogenesis and, thus, cleft palate. We present an epigenetic model of information processing related to cell proliferation. The model is a dynamical network that uses continuous logic to learn its rules from changing conditions.

Animals↗
PubMed1996

Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells: an epigenetic mechanism of tumour progression?

Normal thyroid follicular cells, like many highly differentiated epithelia, have limited proliferative capacity. We previously showed that this could be extended by expression of the SV40 large T oncogene, but that immortal lines always lost thyroid-specific differentiation. Detailed analysis now show that clones expressing T undergo 2 mutually exclusive fates. They either (i) remain well-differentiated, in which case they undergo irreversible growth arrest after 5 to 15 p.d., or (ii) spontaneously develop poorly differentiated sub-clones that exhibit greatly extended proliferative life spans (up to 75 p.d.). The frequency of this event (> 3 per 10(4) cell divisions) greatly exceeds that expected from somatic mutation, suggesting an epigenetic basis. This is supported by our finding of rare de-differentiated epithelial cells in normal thyroid that all generate clones with extended life spans, indistinguishable from the above, following introduction of SV40 T. Escape from early mortality in differentiated thyroid epithelium therefore requires not only loss of tumour suppressor gene function (induced here by SV40 T), but also a switch in differentiation programme, with the latter effectively converting the follicular cell into a cell type with increased intrinsic proliferative potential. The analogy between this in vitro model and the progression of thyroid cancer from the well-differentiated to the highly aggressive, anaplastic form suggests that de-differentiation may play a causal rather than a passive role in this critical switch in tumour behaviour.

Antigens, Viral, Tumor↗
PubMed1996

Epigenetic alterations brought about by lithium treatment disrupt mouse embryo development.

The commonly accepted mechanism by which LiCl dorsalizes amphibian embryos is a respecification of ventral blastomeres, presumably through realignment of dorsal positional information in the embryo. An alternative mechanism, however, is an epigenetic change in the competence of cells to respond to cues they may be normally exposed to without effect. In order to test this hypothesis, we treated mouse preimplantation embryos, which do not possess any axial positional information, with LiCl, and observed axial abnormalities which must have been elaborated several days after treatment. We interpret this as support for the hypothesis that cellular competence rather than positional information is altered by LiCl, and suggest that this competence may be altered through the action of lithium sensitive enzymes that interact with chromatin.

Animals↗
PubMed2001

Detrimental effect of cancer preventive phytochemicals silymarin, genistein and epigallocatechin 3-gallate on epigenetic events in human prostate carcinoma DU145 cells.

BACKGROUND: Targeting epigenetic events associated with autonomous growth of advanced prostate cancer (PCA) is a practical approach for its control, prevention, and treatment. Recently we showed that treatment of prostate carcinoma DU145 cells with cancer preventive flavonoid silymarin at 100-200 microM doses inhibits erbB1-Shc mitogenic signaling and modulates cell cycle regulators leading to a G1 arrest and inhibition of cell growth and anchorage-independent colony formation. Here, we asked the question whether these important findings could be extended to other cancer preventive flavonoids and isoflavones such as epigallocatechin 3-gallate (EGCG) and genistein. METHODS: DU145 cells were treated with similar doses (100-200 microM) of silymarin, genistein or EGCG, cell lysates prepared, and levels of activated signaling molecules (erbB1-Shc-ERK1/2) and cell cycle regulators (CDKIs, CDKs, and cyclins) analyzed employing immunoprecipitation and/or immunoblotting techniques. Cell growth studies were done by cell counting during 5 days of treatment with these agents, and cell death was determined by Trypan blue staining. RESULTS: Treatment of cells with silymarin, genistein or EGCG at 100-200 microM resulted in a complete inhibition of TGFalpha-caused activation of erbB1 followed by a moderate to strong inhibition (10-90%) of Shc activation without an alteration in their protein levels. Silymarin and genistein, but not EGCG, also inhibited (10% to complete) ERK1/2 activation suggesting that these agents impair erbB1-Shc-ERK1/2 signaling in DU145 cells. In other studies, silymarin, genistein or EGCG caused a strong induction of Cip1/p21 (up to 2.4-fold) and Kip1/p27 (up to 150-fold), and a strong decrease in CDK4 (40-90%) but had moderate effect on CDK2, and cyclins D1 and E. An enhanced level of CDKIs also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein or EGCG also resulted in 50-80% cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein showed cytotoxic effect causing 30-40% cell death. A more profound cytotoxic effect was observed with EGCG accounting for 50% cell death at lower doses and complete loss of viability at higher doses. CONCLUSIONS: These results suggest that similar to silymarin, genistein and EGCG also inhibit mitogenic signaling pathway(s) and alter cell cycle regulators, albeit at different levels, leading to growth inhibition and death of advanced and androgen-independent prostate carcinoma cells. More studies are, therefore, needed with these agents to explore their anti-carcinogenic potential against human prostate cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Features of nuclear architecture that influence gene expression in higher eukaryotes: confronting the enigma of epigenetics.

Complex mechanisms that influence gene expression in mammalian cells have been studied intensively over recent years. Genetic elements that control both the tissue specific patterns and levels of gene expression together with the proteins they bind have been characterised in detail and are clearly pivotal in activating pathways of gene expression. But it is also clear that the behaviour of these genetic elements is complicated by epigenetic factors, so that their introduction into cells with the necessary developmental history-and hence appropriate global concentrations of essential transcription factors-will not guarantee the desired levels of transcription. Recent experiments have reinforced this view and confirmed that apparently critical functions performed by defined genetic elements at certain chromosomal sites are not inevitably recapitulated at other chromosomal locations. Hence, a re-evaluation of the function of critical control elements is required using experimental systems that simplify the range of factors arising from local chromatin organisation. In this way, it should be possible to reveal the intricacies of gene expression that might eventually allow us to reproduce natural levels of expression from artificial gene constructs in human cells. J. Cell. Biochem. Suppl. 35:69-77, 2000.

Animals↗
PubMed2026

DNA Methylation Profiling of Pediatric Ectomesenchymoma Supports Embryonal Rhabdomyosarcoma-Like Epigenetic Identity.

Ectomesenchymoma is a rare, biphenotypic pediatric tumor combining rhabdomyoblastic and neuroectodermal differentiation. We characterize two novel cases through integrated genomics and the first report of genome-wide DNA methylation profiling. Both tumors harbored RAS-pathway mutations (HRAS p.Gly13Arg; NRAS p.Gln61His). Methylation analysis, including microdissected components, consistently aligned ectomesenchymoma with the embryonal rhabdomyosarcoma superfamily, revealing a shared myogenic epigenetic program despite neural differentiation. Shared copy-number profiles across distinct histological regions supported a monoclonal origin. Overall, our data support a close biological relationship between ectomesenchymoma and embryonal rhabdomyosarcoma and indicate that RAS-pathway testing and methylation profiling can significantly refine diagnostic precision.

Humans↗
PubMed1987

Epigenetic rules for expression of cell adhesion molecules during morphogenesis.

From very early developmental times, cell adhesion molecules (CAMs) play key roles in linking cells together and regulating cell movement. By virtue of their capacity to link epithelia and condense mesenchyme, CAMs can act as mechanochemical regulators of morphogenesis. In the vertebrate species examined so far, CAMs appear in ordered sequences on cell surfaces during development. In this paper, evidence is reviewed indicating that the sequential expression of CAMs on cell surfaces at a variety of sites of embryonic induction follows a set of modulation rules that are first discernible at early gastrulation. These rules are related to the adhesion of cells in collectives and to the establishment of borders between such collectives. After gastrulation, all mesenchymal conversions employ N-CAM and show changes in its prevalence in a transition N----0----N where 0 means low or undetectable amounts of the CAM (rule I). In contrast, epithelia modulate from a state in which N-CAM and L-CAM appear simultaneously to the expression of only one or the other of these primary CAMs (rule II). At a variety of induction sites, cell collectives obeying rule I are found in proximity to cell collectives obeying rule II. During the morphogenesis of complex structures such as the feather or the optic placode, one can see a recursive application of these rules, reflecting the formation of significant histological boundaries within which the expression of gene products other than CAMs can lead to great morphological diversity. It is suggested that the genes for CAMs are regulated independently from and prior to those specifying intracellular proteins in a given tissue. According to this proposal, the existence of the epigenetic rules governing CAM expression reflects the evolutionary conservation of a key means of establishing tissue and animal form through the mechanochemical regulation of processes such as cell division, movement and death.

Animals↗
PubMed1998

Multiple epigenetic events regulate mating-type switching of fission yeast.

Two epigenetic events at mat1, one of which is DNA strand specific, are required to initiate recombination during mating-type switching. The third, a chromosomally borne imprinted event at the mat2/3 interval regulates silencing and directionality of switching, and prohibits interchromosomal recombination. We speculate that the unit of inheritance in the mat2/3 interval is both DNA plus its associated chromatin structure. Such a control is likely to be essential in maintaining particular states of gene expression during development.

Animals↗
PubMed1975

Control circuits for determination and transdetermination: interpreting positional information in a binary epigenetic code.

Positional information in an embryo requires interpretation to guide spatially ordered differentiation. Evidence, from dtermination and transdetermination among imaginal disc derivatives in Drosophila, suggests the interpretative commitment, or determination, is carried by entities possissing only two alternate states each. This hypothesis correctly predicts pairs of classes of mutants affecting complementary subsets of imaginal discs. Four such complementary pairs define four boundaries separating the various imaginal discs on the fate map of the egg. Crossing any boundary corresponds to a change in state of the associated determination circuit. Using these boundaries, the model makes 43 predictions about relative transdetermination frequencies. Thirty-four appear correct. This has an a priori probability of less than 10- minus 4. False predictions appear to reflect incompleteness in the theory. The four boundaries on the fate map presumably correspond to threshold levels of spatial gradients constituting positional information; on one side of a threshold one circuit state occurs, on the other, the second state. The last four cleavage divisions in Drosophila melanogaster occur as four mitotic waves with geometries similar to the four boundaries. Disc determination happens at about this time. These waves may be, or reflect, the signalling system carrying positional information. Focus on the interpretive machinery, the determination circuits, suggests two slightly new concepts: (1 the set of possible combinations of states of determination circuits constitutes an epigenetic code, thus raising familiar coding questions concerning redundancy or nonsense words; (2) each circuit may respond to its own gradient or positional signal distributed in two or three dimensions.

Animals↗
PubMed2006

Epigenetics and chronic lymphocytic leukemia.

The DNA methylation level in patients with chronic lymphocytic leukemia is generally lower than healthy individuals. Although DNA methylation is globally decreased, regional hypermethylation of gene promoters leads to gene silencing. Many of these genes have tumor suppressor phenotypes. Unlike mutations or deletions, hypermethylation is potentially reversible after inhibition with DNA methylation modulators. Myelodysplastic syndrome has been a model disease in which treatment of patients results in demethylation of specific genes. The story in patients with chronic lymphocytic leukemia is slowly unraveling as epigenetic modifications likely also play an important role. Ongoing clinical trials correlating clinical response to gene expression after treatment with DNA methylation inhibitors will ultimately allow us to better risk stratify and predict the subgroup of patients who will benefit from treatment with this class of drugs.

DNA Methylation↗
PubMed1989

Gestation length, metabolic rate, and body and brain weights in primates: epigenetic effects.

The relationship of brain and body weights can be expressed in log-log regression: log (brain weight) = log (A) + B log (body weight). To investigate further the weights' similarity, gestation length and brain and body weights were determined from the literature for 46 primate genera. The results of allometric and path regression analyses suggest that the relationship between brain and body weights may not be mainly pleiotropic in the order Primates. The correlation between brain and body weights appears to be due to epigenetic factors in hyperplastic growth related to time constraint by gestation length and to energy utilization limitations imposed by metabolic rate.

Animals↗
PubMed2005

Epigenetic reprogramming throughout preimplantation development and consequences for assisted reproductive technologies.

Knowledge about preimplantation development is important both for basic reproductive biology and for practical applications, including livestock breeding and regenerative medicine. During preimplantation development, epigenetic modifications such as DNA methylation and histone modifications are involved in the regulation of imprinted and non-imprinted genes, in the initiation of X chromosome inactivation, and the adjustment of telomere length. The underlying events are particularly vulnerable to external factors. Characterization of expression profiles in in vivo-derived embryos of different developmental stages and understanding the mechanisms and dynamics underlying the reprogramming process are the first steps towards the analysis of the complex gene regulatory networks. They provide a baseline for the analysis of manipulated embryos of all mammalian species, including humans, to improve embryo technologies and related therapeutic applications.

Animals↗
PubMed2003

Checkpoint signaling: epigenetic events sound the DNA strand-breaks alarm to the ATM protein kinase.

The ATM protein kinase is centrally involved in the cellular response to ionizing radiation (IR) and other DNA double-strand-break-inducing insults. Although it has been well established that IR exposure activates the ATM kinase domain, the actual mechanism by which ATM responds to damaged DNA has remained enigmatic. Now, a landmark paper provides strong evidence that DNA-strand breaks trigger widespread activation of ATM through changes in chromatin structure (1). This review discusses a checkpoint activation model in which chromatin perturbations lead to the conversion of inactive ATM domains to phosphorylated, active ATM monomers. The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2006

Eyeing tumorigenesis: Notch signaling and epigenetic silencing of Rb in Drosophila.

Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres-Marco et al. described how they used the Drosophila eye as a model system and found that elevated Notch signaling in combination with activation of components of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor-suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis.

Animals↗
PubMed1995

Epigenetic regulation of the maize Spm transposon.

Expression and transposition of the Suppressor-mutator (Spm) transposon of maize are controlled by interacting epigenetic and autoregulatory mechanisms. Methylation of critical element sequences prevents both transcription and transposition, heritably inactivating the element. The promoter, comprising the terminal 0.2 kb of the element, and a 0.35-kb, highly GC-rich, downstream sequence are the methylation target sequences. The element encodes two proteins necessary for transposition, TnpA and TnpD. There are multiple TnpA binding sites, both in the 5' terminal promoter region and at the element's 3' end. In addition to its role in transposition, TnpA is both a positive and a negative regulator of transcription. TnpA represses the element's promoter when it is not methylated. When the element is inactive and its promoter methylated, TnpA activates the methylated promoter and facilitates both its transient and heritable demethylation.

Base Sequence↗
PubMed2006

Reverting cholesterol auxotrophy of NS0 cells by altering epigenetic gene silencing.

NS0 is a cholesterol-requiring mouse myeloma cell line widely used in the production of recombinant antibodies. We have previously reported that the deficiency of 17beta-hydroxysteroid dehydrogenase type7 (Hsd17b7) is responsible for the cholesterol auxotrophy of NS0 cells. Here we demonstrate DNA methylation to be the mechanism underlying transcriptional suppression of Hsd17b7 in cholesterol dependent NS0 cells. Analysis of the DNA methylation pattern revealed methylation of the CpG-rich region upstream of the Hsd17b7 transcription start site in NS0 cells. This is in contrast to the unmethylated status of this sequence in a naturally isolated cholesterol independent revertant cell population (NS0_r). This transcriptional repression was relieved after treating cells with the demethylating drug, 5-azacytidine. Drug treatment also gave rise to high frequency cholesterol-independent variants. Characterization of revertants revealed substantially elevated transcript level of 17beta-hydroxysteroid dehydrogenase type7 (Hsd17b7) gene along with hypomethylation of the CpG-rich region. These results affirm that deficiency of Hsd17b7 causes cholesterol dependence of NS0 cells. Furthermore, induction of cholesterol independence by altering DNA methylation pattern alludes to the role of epigenetics in the metabolic adaptation of NS0 cells. With the widespread use of NS0 cells, this finding will have a significant impact on the optimization of recombinant antibody production processes.

17-Hydroxysteroid Dehydrogenases↗
PubMed2006

Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus.

BACKGROUND: The CpG island methylator phenotype (CIMP), which is characterized by simultaneous methylation of the CpG islands of multiple genes, has been recognized as one of the important mechanisms in gastrointestinal carcinogenesis. METHODS: Methylation of the 5 methylated-in-tumors (MINT) loci and 12 tumor-related genes in 78 primary gastric carcinomas was examined using combined bisulfite-restriction analysis. Epstein-Barr virus (EBV)-associated gastric tumors were detected using real-time polymerase chain reaction analysis followed by an evaluation of the correlations between CIMP status, EBV-association, and genetic alteration of p53 and K-ras. The authors compared the clinicopathologic features of gastric carcinomas that had high CIMP methylation (CIMP-H) with tumors that had low CIMP methylation (CIMP-L) or negative CIMP methylation (CIMP-N). RESULTS: The methylation profiles of 12 genes showed nonrandom methylation, supporting the presence of CIMP in gastric carcinoma. No p53 mutations were detected among CIMP-H tumors, and no EBV association was detected in tumors that showed mutation of p53 and K-ras. In a multiple logistic regression model with CIMP-H as the dependent variable, proximal location (P = .011), diffuse type (P = .019), and less advanced pathologic TNM status (P = .043) contributed significantly to CIMP-H. Patients who had CIMP-N gastric tumors had a significantly worse survival than patients who had CIMP-H tumors (P = .004) or CIMP-L tumors (P = .012). EBV-associated tumors were associated strongly with CIMP-H, hypermethylation of tumor-related genes, and no p53 or K-ras mutation. CONCLUSIONS: CIMP status appeared to be associated with distinct genetic, epigenetic, and clinicopathologic features in gastric carcinomas. The finding that gastric carcinomas arose through different molecular pathways may affect not only tumor characteristics but also patient prognosis.

Aged↗
PubMed2006

RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma.

BACKGROUND: Allelotype studies have suggested that chromosome 1p is frequently lost in thyroid cancers, thus suggesting that there is an important tumor suppressor at this location. RIZ1 (PRDM2), located on 1p36, is a recently described tumor suppressor gene and is a member of the protein methyltransferase superfamily. RIZ1 expression is lost in a variety of tumors, primarily by means of epigenetic mechanisms that involve promoter hypermethylation. METHODS: RIZ1 expression was examined in a panel of thyroid tumor cell lines and primary thyroid tissues (14 normal, 19 benign, and 31 cancerous) by using real-time polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using bisulfite sequencing and methylation-specific PCR. RESULTS: The authors demonstrated that RIZ1 expression is lost in thyroid tumor cell lines and is also significantly reduced in thyroid carcinomas, when compared with normal thyroid tissues (P < .0001) and benign tumors (P = .0003). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. One hundred percent of carcinomas were methylated, compared with 33% of normal thyroid tissues (P = .001). RIZ1 mRNA expression was significantly higher (P = .02) in unmethylated (1.22 +/- 1.2, mean +/- standard deviation [SD]), compared with methylated tissues (0.37 +/- 0.42, mean +/- SD). Last, treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline. CONCLUSIONS: The current study suggested an important role for RIZ1 expression in thyroid tumorigenesis and identified a potential novel therapeutic target for tumors unresponsive to other therapies.

Antimetabolites, Antineoplastic↗