Hypermethylation of the 5′CpG island of the FHIT gene in clear cell renal carcinomas.


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Kvasha S, Gordiyuk V, Kondratov A, Ugryn D, Zgonnyk YM, Rynditch AV, Vozianov AF
Cancer Lett (Jul 2008)

FHIT is a tumour suppressor gene which is frequently inactivated in different types of cancer. Both genetic (mutations, deletions, chromosomal rearrangements) and epigenetic (aberrant methylation of the 5′CpG island) alterations of the FHIT gene have been reported in various malignancies. Yet little is known about the mechanism of FHIT inactivation in clear cell renal carcinomas. Since genetic alterations were not frequently observed in DNA corresponding to the FHIT gene in renal tumours, to elucidate the mechanism of FHIT gene silencing we examined 22 paired samples of clear cell renal carcinoma and non-malignant renal tissue for the methylation of the FHIT 5′CpG island by methylation-specific PCR. Hypermethylation of the FHIT 5′CpG island was detected in 54.5% (12/22) of clear cell renal carcinomas. Bisulfite sequencing of the FHIT 5′CpG island confirmed the results obtained by methylation-specific PCR for selected samples. We showed here that expression of the FHIT gene is inversely correlated with hypermethylation of the FHIT 5′CpG island in the selected samples. Our results suggest that hypermethylation of the FHIT 5′CpG island may be responsible for inactivation of the FHIT gene in clear cell renal carcinomas.

Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies.


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Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H
Cancer (Jun 2008)

Decitabine (5-aza-2′-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used decitabine as a classical anticancer drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m(2) per course. At these doses, decitabine was found to be active in leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylating) therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at ‘optimal biologic’ doses that modulate hypomethylation). In these dose schedules of decitabine (100 to 150 mg/m(2) per course), the drug was found to be active with manageable side effects in patients with myelodysplastic syndromes (MDS) and other myeloid tumors. Optimizing dosing schedules of decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that decitabine is an active therapy that alters the natural course of MDS. Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies. Cancer 2008. (c)2008 American Cancer Society.

Calculating human exposure to endocrine disrupting pesticides via agricultural and non-agricultural exposure routes.


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McKinlay R, Plant JA, Bell JN, Voulvoulis N
Sci Total Environ (Jul 2008)

Endocrine Disrupting Chemicals (EDCs) are of increasing concern because of their potential impacts on the environment, wildlife and human health. Pesticides and some pesticide metabolites are an important group of EDC, and exposure to them is a poorly quantified source of human and environmental exposure to such chemicals generally. Models for estimating human exposure to Endocrine Disrupting (ED) pesticides are an important risk management tool. Probabilistic models are now being used in addition to deterministic ones in all areas of risk assessment. These can provide more realistic exposure estimates, because they are better able to deal with variation and uncertainty more effectively and better inform risk management decisions. Deterministic models are still used and are of great value where exposure data are scarce. Models or groups of models that provide holistic human ED pesticide exposure estimates are required if the risk posed to humans by ED pesticides is to be better assessed. Much more research is needed to quantify different exposure routes such as exposure from agricultural spray drift and the medical use of pesticides to develop such models. Most available probabilistic models of human exposure were developed in the USA and require modification for use elsewhere. In particular, datasets equivalent to those used to create and apply the American models are required. This paper examines the known routes of human pesticide exposure with particular reference to ED pesticides and their quantification as unlike pesticides generally, many ED pesticides are harmful at very low doses, especially if exposure occurs during sensitive stages of development, producing effects that may not manifest for many years or that affect descendants via epigenetic changes. It also summarises available deterministic and probabilistic models commonly used to calculate human exposure. The main requirement if such models are to be used in the UK is more quantitative data on the sources and pathways of human ED pesticide exposure.

Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins.


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Rosa A, Picchioni MM, Kalidindi S, Loat CS, Knight J, Toulopoulou T, Vonk R, van der Schot AC, Nolen W, Kahn RS, McGuffin P, Murray RM, Craig IW
Am J Med Genet B Neuropsychiatr Genet (Jun 2008)

Monozygotic (MZ) twins may be subject to epigenetic modifications that could result in different patterns of gene expression. Several lines of evidence suggest that epigenetic factors may underlie mental disorders such as bipolar disorder (BD) and schizophrenia (SZ). One important epigenetic modification, of relevance to female MZ twins, is X-chromosome inactivation. Some MZ female twin pairs are discordant for monogenic X linked disorders because of differential X inactivation. We postulated that similar mechanisms may also occur in disorders with more complex inheritance including BD and SZ. Examination of X-chromosome inactivation patterns in DNA samples from blood and/or buccal swabs in a series of 63 female MZ twin pairs concordant or discordant for BD or SZ and healthy MZ controls suggests a potential contribution from X-linked loci to discordance within twin pairs for BD but is inconclusive for SZ. Discordant female bipolar twins showed greater differences in the methylation of the maternal and paternal X alleles than concordant twin pairs and suggest that differential skewing of X-chromosome inactivation may contribute to the discordance observed for bipolar disorder in female MZ twin pairs and the potential involvement of X-linked loci in the disorder.

Heterochromatin tells CENP-A where to go.


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Durand-Dubief M, Ekwall K
Bioessays (Jun 2008)

The centromere is the region of the chromosome where the kinetochore forms. Kinetochores are the attachment sites for spindle microtubules that separate duplicated chromosomes in mitosis and meiosis. Kinetochore formation depends on a special chromatin structure containing the histone H3 variant CENP-A. The epigenetic mechanisms that maintain CENP-A chromatin throughout the cell cycle have been studied extensively but little is known about the mechanism that targets CENP-A to naked centromeric DNA templates. In a recent report published in Science, such de novo centromere assembly of CENP-A is shown to be dependent on heterochromatin and the RNA interference pathway.

Exploring the behavior of small eukaryotic gene networks.


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Bruggeman FJ, Oancea I, van Driel R
J Theor Biol (Jun 2008)

Analysis of the genome organization of higher eukaryotes indicates that it contains many clusters of functionally related genes. In these clusters, the activity of a single gene is regulated hierarchically at a local gene-level and a global cluster-level. Whether a single gene can be activated by a dedicated transcription factor depends on the epigenetic status of the cluster, i.e. whether it is epigenetically permissive or silenced. The consequence of gene clusters for the functioning of gene networks is largely unexplored. The accumulating biological knowledge about mechanisms for epigenetic regulation, signal transduction, and gene clusters makes such explorations a timely challenge. We explore the steady-state behavior of two gene clusters that mutually inhibit each other. This gives rise to multiple steady states in this simple system of interacting clusters. We illustrate that a gene cluster encoding a module composed of a signal transduction network and a transcription factor can generate versatile temporal dynamics that resembles cellular differentiation. The gene cluster can be epigenetically silenced and activated by a dedicated transcription factor. This module displays transient signal sensitivity, and irreversible decisions (commitment; hysteresis) depending on the identity and temporal sequence of external signals.

Characterization of Dnmt3b:thymine-DNA glycosylase interaction and stimulation of thymine glycosylase-mediated repair by DNA methyltransferase(s) and RNA.


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Boland MJ, Christman JK
J Mol Biol (Jun 2008)

Methylation of cytosine residues in CpG dinucleotides plays an important role in epigenetic regulation of gene expression and chromatin structure/stability in higher eukaryotes. DNA methylation patterns are established and maintained at CpG dinucleotides by DNA methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b). In mammals and many other eukaryotes, the CpG dinucleotide is underrepresented in the genome. This loss is postulated to be the result of unrepaired deamination of cytosine and 5-methylcytosine to uracil and thymine, respectively. Two thymine glycosylases are believed to reduce the impact of 5-methylcytosine deamination. G/T mismatch-specific thymine-DNA glycosylase (Tdg) and methyl-CpG binding domain protein 4 can both excise uracil or thymine at U.G and T.G mismatches to initiate base excision repair. Here, we report the characterization of interactions between Dnmt3b and both Tdg and methyl-CpG binding domain protein 4. Our results demonstrate (1) that both Tdg and Dnmt3b are colocalized to heterochromatin and (2) reduction of T.G mismatch repair efficiency upon loss of DNA methyltransferase expression, as well as a requirement for an RNA component for correct T.G mismatch repair.

Epigenetic regulator polycomb group protein complexes control cell fate and cancer.


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Kanno R, Janakiraman H, Kanno M
Cancer Sci (Jun 2008)

The chromatin-associated Polycomb group (PcG) proteins were first identified in genetic screens for homeotic transformations in Drosophila melanogaster. Besides body patterning, members of the PcG are now known to regulate epigenetic cellular memory, stem cell self-renewal, and cancer development. Here, we discuss the multifarious functions of the PcG family, isoforms of protein complexes, and its enzymatic activities, for example histone methylation, links to DNA methylation, its phosphorylation status, H2A mono-ubiquitination, SUMOylation, and links to non-coding RNA. We also discuss the function of cytosolic PcG complexes as a regulator of receptor-induced actin polymerization and proliferation in a methylation-dependent manner. We propose that the functional versatility of PcG protein complexes contributed significantly to the complexity of heritable gene repression mechanisms, signal transduction, and cell proliferation in cancer development.

Epigenetic mechanisms regulating fate specification of neural stem cells.


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Namihira M, Kohyama J, Abematsu M, Nakashima K
Philos Trans R Soc Lond B Biol Sci (Jun 2008)

Neural stem cells (NSCs) possess the ability to self-renew and to differentiate along neuronal and glial lineages. These processes are defined by the dynamic interplay between extracellular cues including cytokine signalling and intracellular programmes such as epigenetic modification. There is increasing evidence that epigenetic mechanisms involving, for example, changes in DNA methylation, histone modification and non-coding RNA expression are closely associated with fate specification of NSCs. These epigenetic alterations could provide coordinated systems for regulating gene expression at each step of neural cell differentiation. Here we review the roles of epigenetics in neural fate specification in the mammalian central nervous system.

Epigenetic remodeling of the fungal secondary metabolome.


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Williams RB, Henrikson JC, Hoover AR, Lee AE, Cichewicz RH
Org Biomol Chem (Jun 2008)

Fungi treated with DNA methyltransferase and histone deacetylase inhibitors exhibited natural product profiles with enhanced chemical diversity demonstrating that small-molecule epigenetic modifiers are effective tools for rationally controlling the native expression of fungal biosynthetic pathways and generating new biomolecules.

Stable long-period cycling and complex dynamics in a single-locus fertility model with genomic imprinting.


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Van Cleve J, Feldman MW
J Math Biol (Aug 2008)

Although long-period population size cycles and chaotic fluctuations in abundance are common in ecological models, such dynamics are uncommon in simple population-genetic models where convergence to a fixed equilibrium is most typical. When genotype-frequency cycling does occur, it is most often due to frequency-dependent selection that results from individual or species interactions. In this paper, we demonstrate that fertility selection and genomic imprinting are sufficient to generate a Hopf bifurcation and complex genotype-frequency cycling in a single-locus population-genetic model. Previous studies have shown that on its own, fertility selection can yield stable two-cycles but not long-period cycling characteristic of a Hopf bifurcation. Genomic imprinting, a molecular mechanism by which the expression of an allele depends on the sex of the donating parent, allows fitness matrices to be nonsymmetric, and this additional flexibility is crucial to the complex dynamics we observe in this fertility selection model. Additionally, we find under certain conditions that stable oscillations and a stable equilibrium point can coexist. These dynamics are characteristic of a Chenciner (generalized Hopf) bifurcation. We believe this model to be the simplest population-genetic model with such dynamics.

Nordihydroguaiaretic acid restores expression of silenced E-cadherin gene in human breast cancer cell lines and xenografts.


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Cui Y, Lu C, Kang A, Liu L, Tan S, Sun D, Hu J, Ma X
Anticancer Drugs (Jun 2008)

In our study we use nordihydroguaiaretic acid (NDGA), the naturally occurring lignan, to investigate whether it plays a role in the prevention and treatment of cancer by epigenetic modifications. The growth inhibitory effect of NDGA on human breast cancer cell lines was determined using the MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay). It substantially inhibited the growth of human breast cancer cell lines SKBR3 and MDA-MB-435 with an estimated IC50 of 31.09+/-1.6 and 38.8+/-2.1 mumol/l respectively, after 4 days incubation with different NDGA concentrations. The in-vivo anticancer activity of NDGA was evaluated by calculating the tumor growth inhibition value. NDGA substantially inhibited the growth of human breast carcinoma cells in both animal and cell-based models. We also found that a single treatment with NDGA reactivates methylation-silenced E-cadherin gene in vitro and in vivo, suggesting an intriguing concept that lignans may act as natural effective epigenetic modifiers in the prevention and treatment of cancer.

Regulation of the nitric oxide pathway genes by tetrahydrofurandiols: Microarray analysis of MCF-7 human breast cancer cells.


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Shoulars K, Rodriguez MA, Thompson T, Turk J, Crowley J, Markaverich BM
Cancer Lett (Jun 2008)

THF-diols (9,12-oxy-10,13-dihydroxyoctadecanoic and 10,13-oxy-9,12-dihydroxyoctadecanoic acids) are endocrine disrupters in rats and mitogens in breast cancer cells. Microarray analyses and real-time PCR analyses on RNA from THF-treated MCF-7 cells revealed a number of genes (caveolin 1, heat shock protein 90alpha and 90beta, vascular endothelial growth factor, ATPase, Ca(++) transporting, ubiquitous) in the nitric oxide pathway (NOP) were targets for THF-diols. Chromatin immunoprecipitation studies suggest THF-diols modify of histone H4 acetylation at the caveolin 1 promoter via an epigenetic mechanism. These findings are consistent with the well-known involvement of NOP genes in cell proliferation and sexual behavior.

Demethylation of (Cytosine-5-C-methyl) DNA and regulation of transcription in the epigenetic pathways of cancer development.


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Patra SK, Patra A, Rizzi F, Ghosh TC, Bettuzzi S
Cancer Metastasis Rev (Jun 2008)

Cancer cells and tissues exhibit genome wide hypomethylation and regional hypermethylation. CpG-methylation of DNA ((Me)CpG-DNA) is defined as the formation of a C-C covalent bond between the 5′-C of cytosine and the -CH(3) group of S-adenosylmethionine. Removal of the sole -CH(3) group from the methylated cytosine of DNA is one of the many ways of DNA-demethylation, which contributes to activation of transcription. The mechanism of demethylation, the candidate enzyme(s) exhibiting direct demethylase activity and associated cofactors are not firmly established. Genome-wide hypomethylation can be obtained in several ways by inactivation of DNMT enzyme activity, including covalent trapping of DNMT by cytosine base analogues. Removal of methyl layer could also be occurred by excision of the 5-methyl cytosine base by DNA glycosylases. The importance of truly chemically defined direct demethylation of intact DNA in regulation of gene expression, development, cell differentiation and transformation are discussed in this contribution.

The aberrant methylation of TSP1 suppresses TGF-beta1 activation in colorectal cancer.


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Rojas A, Meherem S, Kim YH, Washington MK, Willis JE, Markowitz SD, Grady WM
Int J Cancer (Jul 2008)

Colorectal cancer arises from the progressive accumulation of mutations and epigenetic alterations in colon epithelial cells. Such alterations often deregulate signaling pathways that affect the formation of colon cancer, such as the Wnt, RAS-MAPK and TGF-beta pathways. The tumor promoting effects of mutations in genes, such as APC, have been demonstrated in cancer cell lines and in mouse models of intestinal cancer; however, the biological effects of most epigenetic events identified in colorectal cancer remain unknown. Consequently, we assessed whether the aberrant methylation of TSP1, the gene for thrombospondin 1, a regulator of TGF-beta ligand activation, is an epigenetic mechanism for inhibiting the TGF-beta signaling pathway. We found methylated TSP1 occurs in colon cancer cell lines (33%), colon adenomas (14%) and colon adenocarcinomas (21%). In primary colorectal cancers, loss of TSP1 expression correlated with impaired TGF-beta signaling as indicated by decreased Smad2 phosphorylation and nuclear localization. Furthermore, methylation-induced silencing of TSP1 expression reduced the concentration of secreted active TGF-beta1 and attenuated TGF-beta signaling. Reversal of TSP1 methylation resulted in increased TSP1 mediated activation of the latent LAP:TGF-beta complex and subsequent TGF-beta receptor activation. Our results demonstrate that the aberrant methylation of TSP1 has biological consequences and provide evidence that the aberrant methylation of TSP1 is a novel epigenetic mechanism for suppressing TGF-beta signaling in colorectal cancer.