Advertise Here
02.23.08
Posted in research articles at 5:13 pm by admin
Jacobson DJ, Raju NB, Freitag M
Fungal Genet Biol (Mar 2008)
Meiotic silencing by unpaired DNA is a posttranscriptional gene silencing process in Neurospora crassa. Any gene without a homolog in the same chromosomal position during meiotic prophase generates a sequence-specific signal that prevents expression of all copies of that gene, but only during meiosis. Meiotic silencing is epigenetic and involves components of a meiosis-specific RNA silencing machinery. Although N. tetrasperma is closely related to N. crassa, its sexual biology is significantly different. N. tetrasperma was used here to evaluate both the generality of meiotic silencing within the genus and its possible evolutionary significance. A reporter gene for meiotic silencing, a histone H1-GFP fusion construct, was introgressed from N. crassa into various chromosome locations in N. tetrasperma. Whereas we did not observe meiotic silencing in four out of five introgression series, we obtained inconclusive results in the fifth series. Thus, we propose that meiotic silencing in N. tetrasperma is either absent or is substantially reduced when compared to N. crassa, possibly because the sad-1 gene (RNA-directed RNA polymerase, RdRP) is naturally unsynapsed (although “paired”) and self-silenced during meiosis by structural differences between N. tetrasperma mating-type chromosomes. In N. crassa, wild-type sad-1 function is essential for meiotic silencing. Many point mutations in or deletion of sad-1 result in self-silencing of RdRP, and consequently suppression of meiotic silencing in heterozygous asci. The apparent absence or reduced meiotic silencing in N. tetrasperma raises the possibility that this form of silencing is not necessarily a major genome defense mechanism or responsible for reproductive isolation among the species of the genus Neurospora.
Permalink
Posted in research articles at 5:13 pm by admin
O’Regan EM, Toner ME, Finn SP, Fan CY, Ring M, Hagmar B, Timon C, Smyth P, Cahill S, Flavin R, Sheils OM, O’Leary JJ
Hum Pathol (Mar 2008)
Head and neck squamous cell carcinoma (HNSCC) typically affects male smokers older than 55 years. Recently, an increase in the incidence of HNSCC in young adults has been recognized, many of them nonsmokers and females. Functional inactivation of p16 is known to be a common event in HNSCC, mainly by either deletion or methylation. A previous study by this group has shown that p16 deletions in HNSCC are significantly associated with age. The primary objective of this study was to evaluate additional molecular alterations of p16 in HNSCC, specifically in relation to age, site, and human papillomavirus (HPV) status. Patients ranging in age from 22 to 76 years with HNSCC were prospectively identified (n = 24). Methylation-specific polymerase chain reaction and immunohistochemistry were used to evaluate p16 gene inactivation and p16 protein expression, respectively. HPV 16 status was determined for each case. Overall, p16 inactivation was a frequent event detected in 46% of cases. Methylation of p16 was more often detected in females than males (P = .05). All cases showing p16 methylation were from the anterior tongue, and 75% of them were young patients. The results indicate that p16 methylation is a more common event in those younger than 40 years in contrast to p16 deletions, which are more common in those older than 40 years. Consequently, it appears that specific modes of inactivation of p16 in HNSCC are related to specific patient risk profiles. Interestingly, HPV 16 messenger RNA was detected exclusively in HNSCC from the base of tongue lesions and was only found in males. This differs from the patient profile of HNSCC in the young, which affects the anterior tongue and commonly females, thus, making it highly unlikely that this virus is a primary causative agent of HNSCC in these young adults.
Permalink
Posted in research articles at 5:13 pm by admin
Lee JH, Byun DS, Lee MG, Ryu BK, Kang MJ, Chae KS, Lee KY, Kim HJ, Park H, Chi SG
Int J Cancer (Apr 2008)
hSRBC is a putative tumor suppressor located at 11p15.4, at which frequent genomic loss has been observed in several human malignancies. To explore the candidacy of hSRBC as a suppressor of gastric tumorigenesis, we analyzed the expression and mutation status of hSRBC in gastric tissues and cell lines. hSRBC transcript was expressed in all normal and benign tumor tissues examined, but undetectable or very low in 73% (11/15) cancer cell lines and 41% (46/111) primary tumors. Loss or reduction of hSRBC expression was tumor-specific and correlated with stage and grade of tumors. While allelic loss or somatic mutations of the gene were infrequent, its expression was restored in tumor cells by 5-aza-2′-deoxycytidine treatment and aberrant hypermethylation of 23 CpG sites in the promoter region showed a tight association with altered expression. Transient or stable expression of hSRBC led to a G(1) cell cycle arrest and apoptosis of tumor cells, and strongly suppresses colony forming ability and xenograft tumor growth. In addition, hSRBC elevated apoptotic sensitivity of tumor cells to genotoxic agents, such as 5-FU, etoposide and ultraviolet. Interestingly, hSRBC increased the protein stability of p53 and expression of p53 target genes, such as p21(Waf1), PUMA and NOXA, while hSRBC-mediated cell cycle arrest and apoptosis were abolished by blockade of p53 function. Our findings suggest that hSRBC is a novel tumor suppressor whose epigenetic inactivation contributes to the malignant progression of gastric tumors, in part, through attenuated p53 response to stresses.
Permalink
Posted in research articles at 5:13 pm by admin
Liu JH, Yin S, Xiong B, Hou Y, Chen DY, Sun QY
Mol Reprod Dev (Apr 2008)
Genomic imprinting plays a very important role during development and its abnormality may heavily undermine the developmental potential of bovine embryos. Because of limited resources of the cow genome, bovine genomic imprinting, both in normal development and in somatic cell nuclear transfer (SCNT) cloning, is not well documented. DNA methylation is thought to be a major factor for the establishment of genomic imprinting. In our study, we determined the methylation status of differential methylated regions (DMRs) of four imprinted genes in four spontaneously aborted SCNT-cloned fetuses (AF). Firstly, abnormal methylation imprints were observed in each individual to different extents. In particular, Peg3 and MAOA were either seriously demethylated or showed aberrant methylation patterns in four aborted clones we tested, but Xist and Peg10 exhibited relatively better maintained methylation status in AF1 and AF4. Secondly, two aborted fetuses, AF2 and AF3 exhibited severe aberrant methylation imprints of four imprinted genes. Finally, MAOA showed strong heterogeneous methylation patterns of its DMR in normal somatic adult tissue, but largely variable methylation levels and relatively homogeneous methylation patterns in aborted cloned fetuses. Our data indicate that the aborted cloned fetuses exhibited abnormal methylation imprints, to different extent, in aborted clones, which partially account for the higher abortion and developmental abnormalities during bovine cloning. Mol. Reprod. Dev. 75: 598-607, 2008. (c) 2007 Wiley-Liss, Inc.
Permalink
Posted in research articles at 5:13 pm by admin
Romero-Gimnez J, Dopeso H, Blanco I, Guerra-Moreno A, Gonzalez S, Vogt S, Aretz S, Schwartz S, Capella G, Arango D
Int J Cancer (Mar 2008)
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing to colorectal cancer and affects 1 in 5-10,000 births. Inheritance of a mutant allele of the adenomatous polyposis coli (APC) gene is the cause of approximately 80% of FAP and 20-30% of an attenuated form of FAP (AFAP), whereas mutations in MUTYH account for a small proportion of the remaining cases. However, the genetic cause of FAP/AFAP in a significant number of families is not known, and cancer risk for individual members of these families cannot be assessed. There is, therefore, an acute need to identify the underlying genetic cause responsible for FAP/AFAP in APC/MUTYH mutation negative families. Hypermethylation of CpG islands in the promoter of tumor suppressor genes can result in gene silencing, has been shown to be functionally equivalent to genetic mutations and can be inherited. Moreover, APC promoter hypermethylation is observed in approximately 20% of sporadic colorectal tumors and correlates with the loss of gene expression. In our study, we used bisulfite treatment and direct sequencing of 2 regulatory regions of APC containing a total of 25 CpG dinucleotides, to investigate the possible role of germline hypermethylation of the APC promoter in FAP and AFAP families that were negative for APC and MUTYH mutations. Analysis of 21 FAP and 39 AFAP families did not identify signs of abnormal promoter methylation, indicating that this form of epigenetic silencing is not a common cause of FAP/AFAP. These results substantially contribute to clarify the potential role of germline epimutations as a cause of inherited predisposition to cancer.
Permalink
Posted in research articles at 5:13 pm by admin
Taylor J, Hickson J, Lotan T, Yamada DS, Rinker-Schaeffer C
Cancer Metastasis Rev (Mar 2008)
Cancer metastasis is a complex, dynamic process that begins with dissemination of cells from the primary tumor and culminates in the formation of clinically detectable, overt metastases at one or more discontinuous secondary sites. Evidence from in vivo video microscopy as well as PCR and immunohistochemical studies suggest that cancer cell dissemination is an early event in tumor progression and that cells may persist in a potentially dormant state for a prolonged period. Similarly, the mechanisms by which these disseminated cells initiate growth and complete the process of metastatic colonization remain largely unknown. Understanding signal transduction pathways regulating this final step of metastasis is therefore critical for successful clinical management. While genetic mutations or epigenetic changes may be required for a cell or group of cells to separate and survive distant from the primary tumor, the microenvironment within secondary tissues plays a substantial role in influencing whether disseminated cells survive and proliferate. Our work is focused on using metastasis suppressor proteins to gain insight into why the majority of disseminated cells, which should be fully malignant, do not proliferate immediately at secondary sites. The translational goal of this work is to identify targets for inhibiting metastatic growth and prolonging disease-free survival.
Permalink
Posted in research articles at 5:13 pm by admin
de Jong J, Stoop H, Gillis AJ, Hersmus R, van Gurp RJ, van de Geijn GJ, van Drunen E, Beverloo HB, Schneider DT, Sherlock JK, Baeten J, Kitazawa S, van Zoelen EJ, van Roozendaal K, Oosterhuis JW, Looijenga LH
Genes Chromosomes Cancer (Mar 2008)
Testicular germ cell tumors of adolescents and adults (TGCTs) can be classified into seminomatous and nonseminomatous tumors. Various nonseminomatous cell lines, predominantly embryonal carcinoma, have been established and proven to be valuable for pathobiological and clinical studies. So far, no cell lines have been derived from seminoma which constitutes more than 50% of invasive TGCTs. Such a cell line is essential for experimental investigation of biological characteristics of the cell of origin of TGCTs, i.e., carcinoma in situ of the testis, which shows characteristics of a seminoma cell. Before a cell line can be used as model, it must be verified regarding its origin and characteristics. Therefore, a multidisciplinary approach was undertaken on TCam-2 cells, supposedly the first seminoma cell line. Fluorescence in situ hybridization, array comparative genomic hybridization, and spectral karyotyping demonstrated an aneuploid DNA content, with gain of 12p, characteristic for TGCTs. Genome wide mRNA and microRNA expression profiling supported the seminoma origin, in line with the biallelic expression of imprinted genes IGF2/H19 and associated demethylation of the imprinting control region. Moreover, the presence of specific markers, demonstrated by immunohistochemistry, including (wild type) KIT, stem cell factor, placental alkaline phosphatase, OCT3/4 (also demonstrated by a specific Q-PCR) and NANOG, and the absence of CD30, SSX2-4, and SOX2, confirms that TCam-2 is a seminoma cell line. Although mutations in oncogenes and tumor suppressor genes are rather rare in TGCTs, TCam-2 had a mutated BRAF gene (V600E), which likely explains the fact that these cells could be propagated in vitro. In conclusion, TCam-2 is the first well-characterized seminoma-derived cell line, with an exceptional mutation, rarely found in TGCTs.
Permalink
Posted in research articles at 5:13 pm by admin
Yang N, Coukos G, Zhang L
Int J Cancer (Mar 2008)
MicroRNAs (miRNAs) are approximately 22 nt non-coding RNAs, which regulate gene expression in a sequence-specific manner via translational inhibition or messenger RNA (mRNA) degradation. Since the discovery of their fundamental mechanisms of action, the field of miRNAs has opened a new era in the understanding of small noncoding RNAs. By molecular cloning and bioinformatic approaches, miRNAs have been identified in viruses, plants and animals. miRNAs are predicted to negatively target up to one-third of human mRNAs. Cancer is a complex genetic disease caused by abnormalities in gene structure and expression. Previous studies have heavily focused on protein-coding genes; however, accumulating evidence is revealing an important role of miRNAs in cancer. Epigenetics is defined as mitotically and/or meiotically heritable changes in gene expression that are not accompanied by changes in DNA sequence. Given the critical roles of miRNAs and epigenetics in cancer, characterizing the epigenetic regulation of miRNAs will provide novel opportunities for the development of cancer biomarkers and/or the identification of new therapeutic targets in the foreseeable future.
Permalink
02.05.08
Posted in site news at 8:41 am by Trevor
It has become apparent that I have been stretched too thin and am unable to make any significant time contribution to work on this blog. I want to thank all of the readers for following and supporting the site along the way, and I hope that this will inspire someone with the time and energy to start their own blog about epigenetics. I may do another blog in the future, but it will not be right now as I am focused on finishing my undergraduate degree and moving on to graduate school.
Thank you again!
Trevor Covert
Tags: goodbye
Permalink
Next entries »
