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Nickel and Epigenetic Gene Silencing  [PDF]
Hong Sun,Magdy Shamy,Max Costa
Genes , 2013, DOI: 10.3390/genes4040583
Abstract: Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.
Characterization of Tumor Suppressive Function of cornulin in Esophageal Squamous Cell Carcinoma  [PDF]
Kai Chen, Yan Li, Yongdong Dai, Jiangchao Li, Yanru Qin, Yinghui Zhu, Tingting Zeng, Xiaojiao Ban, Li Fu, Xin-Yuan Guan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068838
Abstract: By using cDNA microarray analysis, we identified cornulin (CRNN) gene was frequently downregulated in esophageal squamous cell carcinoma (ESCC). In the present study, we investigated the role of CRNN in ESCC development. The results showed that CRNN was frequently downregulated in primary ESCCs in both mRNA level (26/56, 46.4%) and protein level (137/249, 55%), which was significantly associated with lymph node metastases (P=0.027), advanced clinical stage (P=0.039), and overall survival rate (P<0.001). Multivariate analysis indicated that the CRNN downregulation was an independent prognostic factor for ESCC. Functional studies with both in vitro and in vivo assays demonstrated that CRNN had strong tumor suppressive ability in ESCC cells. The tumor-suppressive mechanism of CRNN was associated with its role in cell cycle arrest at G1/S checkpoint by upregulating expressions of P21WAF1/CIP1 and Rb. Silencing CRNN expression by RNA interference could effectively inhibit its tumor suppressive effect. In conclusion, our findings demonstrate that CRNN is a tumor suppressor gene that plays a critical tumor suppressive role in ESCC.
Titration and hysteresis in epigenetic chromatin silencing  [PDF]
Adel Dayarian,Anirvan M. Sengupta
Quantitative Biology , 2012, DOI: 10.1088/1478-3975/10/3/036005
Abstract: Epigenetic mechanisms of silencing via heritable chromatin modifications play a major role in gene regulation and cell fate specification. We consider a model of epigenetic chromatin silencing in budding yeast and study the bifurcation diagram and characterize the bistable and the monostable regimes. The main focus of this paper is to examine how the perturbations altering the activity of histone modifying enzymes affect the epigenetic states. We analyze the implications of having the total number of silencing proteins given by the sum of proteins bound to the nucleosomes and the ones available in the ambient to be constant. This constraint couples different regions of chromatin through the shared reservoir of ambient silencing proteins. We show that the response of the system to perturbations depends dramatically on the titration effect caused by the above constraint. In particular, for a certain range of overall abundance of silencing proteins, the hysteresis loop changes qualitatively with certain jump replaced by continuous merger of different states. In addition, we find a nonmonotonic dependence of gene expression on the rate of histone deacetylation activity of Sir2. We discuss how these qualitative predictions of our model could be compared with experimental studies of the yeast system under anti-silencing drugs.
Genetic and Epigenetic Somatic Alterations in Head and Neck Squamous Cell Carcinomas Are Globally Coordinated but Not Locally Targeted  [PDF]
Graham M. Poage,Brock C. Christensen,E. Andres Houseman,Michael D. McClean,John K. Wiencke,Marshall R. Posner,John R. Clark,Heather H. Nelson,Carmen J. Marsit,Karl T. Kelsey
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009651
Abstract: Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Little work has been done that simultaneously examines the spectrum of both types of changes in human tumors on a genome-wide scale and results so far have been limited and mixed. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC.
Epigenetic Chromatin Silencing: Bistability and Front Propagation  [PDF]
Mohammad Sedighi,Anirvan M. Sengupta
Quantitative Biology , 2007, DOI: 10.1088/1478-3975/4/4/002
Abstract: The role of post-translational modification of histones in eukaryotic gene regulation is well recognized. Epigenetic silencing of genes via heritable chromatin modifications plays a major role in cell fate specification in higher organisms. We formulate a coarse-grained model of chromatin silencing in yeast and study the conditions under which the system becomes bistable, allowing for different epigenetic states. We also study the dynamics of the boundary between the two locally stable states of chromatin: silenced and unsilenced. The model could be of use in guiding the discussion on chromatin silencing in general. In the context of silencing in budding yeast, it helps us understand the phenotype of various mutants, some of which may be non-trivial to see without the help of a mathematical model. One such example is a mutation that reduces the rate of background acetylation of particular histone side-chains that competes with the deacetylation by Sir2p. The resulting negative feedback due to a Sir protein depletion effect gives rise to interesting counter-intuitive consequences. Our mathematical analysis brings forth the different dynamical behaviors possible within the same molecular model and guides the formulation of more refined hypotheses that could be addressed experimentally.
A Position Effect on the Heritability of Epigenetic Silencing  [PDF]
Jaswinder Singh,Michael Freeling,Damon Lisch
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000216
Abstract: In animals and yeast, position effects have been well documented. In animals, the best example of this process is Position Effect Variegation (PEV) in Drosophila melanogaster. In PEV, when genes are moved into close proximity to constitutive heterochromatin, their expression can become unstable, resulting in variegated patches of gene expression. This process is regulated by a variety of proteins implicated in both chromatin remodeling and RNAi-based silencing. A similar phenomenon is observed when transgenes are inserted into heterochromatic regions in fission yeast. In contrast, there are few examples of position effects in plants, and there are no documented examples in either plants or animals for positions that are associated with the reversal of previously established silenced states. MuDR transposons in maize can be heritably silenced by a naturally occurring rearranged version of MuDR. This element, Muk, produces a long hairpin RNA molecule that can trigger DNA methylation and heritable silencing of one or many MuDR elements. In most cases, MuDR elements remain inactive even after Muk segregates away. Thus, Muk-induced silencing involves a directed and heritable change in gene activity in the absence of changes in DNA sequence. Using classical genetic analysis, we have identified an exceptional position at which MuDR element silencing is unstable. Muk effectively silences the MuDR element at this position. However, after Muk is segregated away, element activity is restored. This restoration is accompanied by a reversal of DNA methylation. To our knowledge, this is the first documented example of a position effect that is associated with the reversal of epigenetic silencing. This observation suggests that there are cis-acting sequences that alter the propensity of an epigenetically silenced gene to remain inactive. This raises the interesting possibility that an important feature of local chromatin environments may be the capacity to erase previously established epigenetic marks.
Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer
Valgerdur Birgisdottir, Olafur A Stefansson, Sigridur K Bodvarsdottir, Holmfridur Hilmarsdottir, Jon G Jonasson, Jorunn E Eyfjord
Breast Cancer Research , 2006, DOI: 10.1186/bcr1522
Abstract: Primary sporadic breast tumours were analysed for BRCA1α promoter methylation by methylation specific PCR and for allelic imbalance (AI) at BRCA1 and BRCA2 loci by microsatellite analysis and TP53 (also known as p53) mutations by constant denaturing gel electrophoresis. The BRCA1 methylated tumours were analysed for BRCA1 copy alterations by fluorescence in situ hybridisation and BRCA1 expression by immunostaining.BRCA1 methylation was found in 13/143 (9.1%) sporadic breast tumours. The BRCA1 methylated tumours were significantly associated with estrogen receptor (ER) negativity (P = 0.0475) and displayed a trend for BRCA1 AI (P = 0.0731) as well as young-age at diagnosis (≤ 55; P = 0.0898). BRCA1 methylation was not associated with BRCA2 AI (P = 0.5420), although a significant association was found between BRCA1 AI and BRCA2 AI (P < 0.0001).Absent/markedly reduced BRCA1 expression was observed in 9/13 BRCA1 methylated tumours, most of which had BRCA1 deletion. An elevated TP53 mutation frequency was found among BRCA1 methylated tumours (38.5%) compared with non-methylated tumours (17.2%). The BRCA1 methylated tumours were mainly of tumour grade 3 (7/13) and infiltrating ductal type (12/13). Only one methylated tumour was of grade 1.BRCA1 methylation is frequent in primary sporadic breast tumours. We found an indication for BRCA1 methylation to be associated with AI at the BRCA1 locus. Almost all BRCA1 methylated tumours with absent/markedly reduced BRCA1 expression (8/9) displayed BRCA1 deletion. Thus, epigenetic silencing and deletion of the BRCA1 gene might serve as Knudson's two 'hits' in sporadic breast tumorigenesis. We observed phenotypic similarities between BRCA1 methylated and familial BRCA1 tumours, based on BRCA1 deletion, TP53 mutations, ER status, young age at diagnosis and tumour grade.Germline mutations in one allele of the BRCA1 or BRCA2 genes significantly increase the risk of developing early-onset breast cancer [1]. Tumour cells from predisposed
Epigenetic Silencing of Nucleolar rRNA Genes in Alzheimer's Disease  [PDF]
Maciej Pietrzak,Grzegorz Rempala,Peter T. Nelson,Jing-Juan Zheng,Michal Hetman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022585
Abstract: Ribosomal deficits are documented in mild cognitive impairment (MCI), which often represents an early stage Alzheimer's disease (AD), as well as in advanced AD. The nucleolar rRNA genes (rDNA), transcription of which is critical for ribosomal biogenesis, are regulated by epigenetic silencing including promoter CpG methylation.
Aberrant Epigenetic Silencing Is Triggered by a Transient Reduction in Gene Expression  [PDF]
Jon A. Oyer, Adrian Chu, Sukhmani Brar, Mitchell S. Turker
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004832
Abstract: Background Aberrant epigenetic silencing plays a major role in cancer formation by inactivating tumor suppressor genes. While the endpoints of aberrant silencing are known, i.e., promoter region DNA methylation and altered histone modifications, the triggers of silencing are not known. We used the tet-off system to test the hypothesis that a transient reduction in gene expression will sensitize a promoter to undergo epigenetic silencing. Methodology/Principal Findings The tet responsive promoter (PTRE) was used to drive expression of the selectable human HPRT cDNA in independent transfectants of an Hprt deficient mouse cell line. In this system, high basal HPRT expression is greatly reduced when doxycycline (Dox) is added to the culture medium. Exposure of the PTRE-HPRT transfectants to Dox induced HPRT deficient clones in a time dependent manner. A molecular analysis demonstrated promoter region DNA methylation, loss of histone modifications associated with expression (i.e., H3 lysine 9 and 14 acetylation and lysine 4 methylation), and acquisition of the repressive histone modification H3 lysine 9 methylation. These changes, which are consistent with aberrant epigenetic silencing, were not present in the Dox-treated cultures, with the exception of reduced H3 lysine 14 acetylation. Silenced alleles readily reactivated spontaneously or after treatment of cells with inhibitors of histone deacetylation and/or DNA methylation, but re-silencing of reactivated alleles did not require a new round of Dox exposure. Inhibition of histone deacetylation inhibited both the induction of silencing and re-silencing, whereas inhibition of DNA methylation had no such effect. Conclusions/Significance This study demonstrates that a transient reduction in gene expression triggers a pathway for aberrant silencing in mammalian cells and identifies histone deacetylation as a critical early step in this process. DNA methylation, in contrast, is a secondary step in the silencing pathway under study. A model to explain these observations is offered.
Epigenetic Dysregulation in Laryngeal Squamous Cell Carcinoma  [PDF]
Thian-Sze Wong,Wei Gao,Zeng-Hong Li,Jimmy Yu-Wai Chan,Wai-Kuen Ho
Journal of Oncology , 2012, DOI: 10.1155/2012/739461
Abstract: Laryngeal carcinoma is a common head and neck cancer with poor prognosis. Patients with laryngeal carcinoma usually present late leading to the reduced treatment efficacy and high rate of recurrence. Despite the advance in the use of molecular markers for monitoring human cancers in the past decades, there are still no reliable markers for use to screen laryngeal carcinoma and follow the patients after treatment. Epigenetics emerged as an important field in understanding the biology of the human malignancies. Epigenetic alterations refer to the dysregulation of gene, which do not involve the alterations of the DNA sequence. Major epigenetic changes including methylation imbalance, histone modification, and small RNA dysregulation could play a role in the development of human malignancies. Global epigenetic change is now regarded as a molecular signature of cancer. The characteristics and behavior of a cancer could be predicted based on the specific epigenetic pattern. We here provide a review on the understanding of epigenetic dysregulation in laryngeal carcinoma. Further knowledge on the initiation and progression of laryngeal carcinoma at epigenetic level could promote the translation of the knowledge to clinical use. 1. Introduction Head and neck squamous carcinoma is estimated to be the sixth most common malignant tumor worldwide. Of which, laryngeal carcinoma is the second most common head and neck squamous carcinoma [1]. According to the global cancer statistics in 2008, the age-standardized incidence rate (ranged from age 0–74) is 5.5 per 100,000 in men and 0.6 per 100,000 in women in developed areas; in less developed area, the incidence rate is 3.5 per 100,000 in men and 0.6 per 100,000 in women [2]. It is estimated that there are 12,740 new patients (male 10,160 and female 2,580, resp.) suffering from laryngeal carcinoma in the United States in 2011 (accounting for 0.7% of the total new cancer cases). It also accounts for about 0.6% estimated cancer-related deaths in the United States [3]. In Hong Kong, laryngeal carcinoma took the third place in the incidence of the head and neck cancer in 2009 [4]. Most of the laryngeal carcinoma patients are male [5]. Moreover, the majority of the patients lie in the middle-aged group [6]. The definite cause of laryngeal carcinoma is not yet determined, while some risk factors are believed to be linked with the development of the disease. Tobacco and alcohol consumption are the primary aetiologic factors [6–8]. Chronic laryngeal inflammation induced by irritants and prolonged voice abuse could also
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