Recent Articles
Heterochromatin tells CENP-A where to go.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
May 29, 2008 research articles Comments Off
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.
Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine.
May 29, 2008 research articles Comments Off
Stresemann C, Lyko F
Int J Cancer (Jul 2008)
The cytosine analogues 5-azacytosine (azacytidine) and 2′-deoxy-5-azacytidine (decitabine) are the currently most advanced drugs for epigenetic cancer therapies. These compounds function as DNA methyltransferase inhibitors and have shown substantial potency in reactivating epigenetically silenced tumor suppressor genes in vitro. However, it has been difficult to define the mode of action of these drugs in patients and it appears that clinical responses are influenced both by epigenetic alterations and by apoptosis induction. To maximize the clinical efficacy of azacytidine and decitabine it will be important to understand the molecular changes induced by these drugs. In this review, we examine the pharmacological properties of azanucleosides and their interactions with various cellular pathways. Because azacytidine and decitabine are prodrugs, an understanding of the cellular mechanisms mediating transmembrane transport and metabolic activation will be critically important for optimizing patient responses. We also discuss the mechanism of DNA methyltransferase inhibition and emphasize the need for the identification of predictive biomarkers for the further advancement of epigenetic therapies.
Lung cancer epigenetics and genetics.
May 29, 2008 research articles Comments Off
Risch A, Plass C
Int J Cancer (Jul 2008)
Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penetrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future.
Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia.
May 29, 2008 research articles Comments Off
Ghoshal Gupta S, Baumann H, Wetzler M
Leuk Res (Jul 2008)
We have demonstrated that constitutive signal transducer and activator of transcription (STAT) 3 activity, observed in approximately 50% of acute myeloid leukemia (AML) cases, is associated with adverse treatment outcome. Constitutive STAT3 activation may result from the expression of oncogenic protein tyrosine kinases or from autocrine stimulation by hematopoietic growth factors. These causes are generally neither necessary nor sufficient for leukemogenesis; additional transforming events or growth stimulatory processes are needed. Here we review the literature addressing epigenetic regulation as a mechanism controlling STAT3 signaling in AML. A better understanding of mechanisms of dysregulation of STAT signaling pathways may serve as a basis for designing novel therapeutic strategies that target these pathways in leukemia cells.
Epigenetic and genetic analysis of the survivin promoter in acute myeloid leukemia.
May 29, 2008 research articles Comments Off
Wagner M, Schmelz K, Drken B, Tamm I
Leuk Res (Jul 2008)
Survivin, an inhibitor of apoptosis (IAP) protein plays a dual role in regulation of mitosis and inhibition of apoptosis. Survivin is expressed in embryonic and fetal organs as well as in most human cancers, but not in normal differentiated adult tissues. In this study we investigated the molecular mechanism involved in overexpression of survivin in acute myeloid leukemia (AML). We used methylation specific PCR (MSP) and bisulfite sequencing to analyze the methylation status of the survivin promoter in primary AML samples and normal peripheral blood mononuclear cells (PBMCs). Both, in patients with de novo AML and normal control samples an unmethylated survivin promoter was present. Mutational analysis of the proximal survivin promoter revealed three single nucleotide polymorphisms (SNPs), where the frequently occurred polymorphism (G/C) at position -31 was detectable in both, AML blasts and healthy PBMCs and showed no significant impact on prognosis in de novo AML patients. These results suggest that the methylation status of the survivin promoter and occurrence of these SNPs within the promoter region of the survivin gene appear to be of minor importance in leukemogenesis.
