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1.  Epigenetics: An emerging player in gastric cancer 
Cancers, like other diseases, arise from gene mutations and/or altered gene expression, which eventually cause dysregulation of numerous proteins and noncoding RNAs. Changes in gene expression, i.e., upregulation of oncogenes and/or downregulation of tumor suppressor genes, can be generated not only by genetic and environmental factors but also by epigenetic factors, which are inheritable but nongenetic modifications of cellular chromosome components. Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies. The search for genetic and environmental factors has a long history in cancer research, but epigenetic factors only recently began to be associated with cancer formation, progression, and metastasis. Epigenetic alterations of chromatin include DNA methylation and histone modifications, which can affect gene-expression profiles. Recent studies have revealed diverse mechanisms by which chromatin modifiers, including writers, erasers and readers of the aforementioned modifications, contribute to the formation and progression of cancer. Furthermore, functional RNAs, such as microRNAs and long noncoding RNAs, have also been identified as key players in these processes. This review highlights recent findings concerning the epigenetic alterations associated with cancers, especially gastric cancer.
PMCID: PMC4047329  PMID: 24914365
Gastric cancer; Epigenetics; DNA methylation; Histone modification; Gene expression
2.  Analysis of an extended chromosome locus 2p14–21 for replication of the 2p16.3 association with glaucoma susceptibility 
Molecular Vision  2011;17:1136-1143.
Susceptibility to primary open-angle glaucoma (POAG) has recently associated with three intergenic single-nucleotide polymorphisms (SNPs) on human chromosome 2p16.3, just outside of the POAG-linkage locus GLC1H (2p15–16.2), in an Afro-Caribbean population. Especially, association of one SNP (rs12994401) was very strong (odds ratio 35) and later replicated in Afro-Americans but not in Ghanaians or Japanese. An extended region was examined in this study to look for SNPs of cross-population association.
The three reported SNPs and all 63 SNPs considerably correlating with rs12994401 (r2≥0.3) in the African-descendent Yoruba were examined for POAG susceptibility association in a Korean population of 1,159 unrelated participants including 226 cases with glaucoma. As these 66 SNPs were spread from 2p14 to 2p21, all SNPs in this extended region were imputed for susceptibility association tests.
No susceptibility association was detected with rs12994401 in comparisons between 933 controls and 188 POAG (or 175 high-tension glaucoma) cases (statistical power of 100%), as well as with all 19 other typed SNPs, using logistic regression with adjustment for age and gender. The other 46 SNPs were deemed non-polymorphic in Koreans. Among 21,201 SNPs located in 2p14–21, only 4,260 were imputed to be non-monomorphic, but none of them passed a significance level of multiple testing. No association was observed when the samples were stratified by age or gender.
No typed or imputed SNPs within 2p14–21 showed association with susceptibility to POAG, suggesting that the population inconsistency in 2p16.3 association was unlikely due to linkage disequilibrium differences.
PMCID: PMC3087448  PMID: 21552472
3.  Accurate quantification of transcriptome from RNA-Seq data by effective length normalization 
Nucleic Acids Research  2010;39(2):e9.
We propose a novel, efficient and intuitive approach of estimating mRNA abundances from the whole transcriptome shotgun sequencing (RNA-Seq) data. Our method, NEUMA (Normalization by Expected Uniquely Mappable Area), is based on effective length normalization using uniquely mappable areas of gene and mRNA isoform models. Using the known transcriptome sequence model such as RefSeq, NEUMA pre-computes the numbers of all possible gene-wise and isoform-wise informative reads: the former being sequences mapped to all mRNA isoforms of a single gene exclusively and the latter uniquely mapped to a single mRNA isoform. The results are used to estimate the effective length of genes and transcripts, taking experimental distributions of fragment size into consideration. Quantitative RT–PCR based on 27 randomly selected genes in two human cell lines and computer simulation experiments demonstrated superior accuracy of NEUMA over other recently developed methods. NEUMA covers a large proportion of genes and mRNA isoforms and offers a measure of consistency (‘consistency coefficient’) for each gene between an independently measured gene-wise level and the sum of the isoform levels. NEUMA is applicable to both paired-end and single-end RNA-Seq data. We propose that NEUMA could make a standard method in quantifying gene transcript levels from RNA-Seq data.
PMCID: PMC3025570  PMID: 21059678
4.  Peptidyl arginine deiminase type IV (PADI4) haplotypes interact with shared epitope regardless of anti-cyclic citrullinated peptide antibody or erosive joint status in rheumatoid arthritis: a case control study 
Arthritis Research & Therapy  2010;12(3):R115.
Anti-cyclic citrullinated peptide autoantibodies (anti-CCP) are the most specific serologic marker for rheumatoid arthritis (RA). Genetic polymorphisms in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations. We investigated whether PADI4 polymorphisms contribute to anti-CCP-negative as well as -positive RA, whether they influence disease severity (erosive joint status), and whether they interact with two major risk factors for RA, Human Leukocyte Antigen-DRB1 (HLA-DRB1) shared epitope (SE) alleles and smoking, depending on anti-CCP and erosive joint status.
All 2,317 unrelated Korean subjects including 1,313 patients with RA and 1,004 unaffected controls were genotyped for three nonsynonymous (padi4_89, padi4_90, and padi4_92) and one synonymous (padi4_104) single-nucleotide polymorphisms (SNPs) in PADI4 and for HLA-DRB1 by direct DNA sequence analysis. Odds ratios (OR) were calculated by multivariate logistic regression. Interaction was evaluated by attributable proportions (AP), with 95% confidence intervals (CI).
A functional haplotype of the three fully correlated nonsynonymous SNPs in PADI4 was significantly associated with susceptibility to not only anti-CCP-positive (adjusted OR 1.73, 95% CI 1.34 to 2.23) but also -negative RA (adjusted OR 1.75, 95% CI 1.15 to 2.68). A strong association with both non-erosive (adjusted OR 1.62, 95% CI 1.29 to 2.05) and erosive RA (adjusted OR 1.62, 95% CI 1.14 to 2.31) was observed for PADI4 haplotype. Gene-gene interactions between the homozygous RA-risk PADI4 haplotype and SE alleles were significant in both anti-CCP-positive (AP 0.45, 95% CI 0.20 to 0.71) and -negative RA (AP 0.61, 95% CI 0.29 to 0.92). Theses interactions were also observed for both non-erosive (AP 0.48, 95% CI 0.25 to 0.72) and erosive RA (AP 0.46, 95% CI 0.14 to 0.78). In contrast, no interaction was observed between smoking and PADI4 polymorphisms.
A haplotype of nonsynonymous SNPs in PADI4 contributes to development of RA regardless of anti-CCP or erosive joint status. The homozygous PADI4 haplotype contribution is affected by gene-gene interactions with HLA-DRB1 SE alleles.
PMCID: PMC2911908  PMID: 20537173
5.  Tiny abortive initiation transcripts exert antitermination activity on an RNA hairpin-dependent intrinsic terminator 
Nucleic Acids Research  2010;38(18):6045-6053.
No biological function has been identified for tiny RNA transcripts that are abortively and repetitiously released from initiation complexes of RNA polymerase in vitro and in vivo to date. In this study, we show that abortive initiation affects termination in transcription of bacteriophage T7 gene 10. Specifically, abortive transcripts produced from promoter ϕ10 exert trans-acting antitermination activity on terminator Tϕ both in vitro and in vivo. Following abortive initiation cycling of T7 RNA polymerase at ϕ10, short G-rich and oligo(G) RNAs were produced and both specifically sequestered 5- and 6-nt C + U stretch sequences, consequently interfering with terminator hairpin formation. This antitermination activity depended on sequence-specific hybridization of abortive transcripts with the 5′ but not 3′ half of Tϕ RNA. Antitermination was abolished when Tϕ was mutated to lack a C + U stretch, but restored when abortive transcript sequence was additionally modified to complement the mutation in Tϕ, both in vitro and in vivo. Antitermination was enhanced in vivo when the abortive transcript concentration was increased via overproduction of RNA polymerase or ribonuclease deficiency. Accordingly, antitermination activity exerted on Tϕ by abortive transcripts should facilitate expression of Tϕ-downstream promoter-less genes 11 and 12 in T7 infection of Escherichia coli.
PMCID: PMC2952870  PMID: 20507918
6.  Relative Codon Adaptation Index, a Sensitive Measure of Codon Usage Bias 
We propose a simple, sensitive measure of synonymous codon usage bias, the Relative Codon Adaptation Index (rCAI), as a way to discriminate better between highly biased and unbiased regions, compared with the widely used Codon Adaptation Index (CAI). CAI is a geometric mean of the relative usage of codons in a gene, and is calculated using the codon usage table trained with a set of highly expressed genes. In contrast, rCAI is computed by subtracting the background codon usage trained with two noncoding frames of highly expressed genes from the codon usage in the coding frame. rCAI has higher signal-to-noise ratio than CAI, considering that noncoding frames would not show codon bias. Translation efficiency and protein abundance correlates comparably or better with rCAI than CAI or other measures such as ‘effective number of codons’ and ‘SCUMBLE offsets’. Within overlapping coding regions, one of the two coding frames dominates in codon usage bias according to rCAI. Presumably, rCAI could substitute CAI in diverse applications.
PMCID: PMC2880845  PMID: 20535230
codon usage bias; codon adaptation index; translation efficiency; overlapping genes
7.  A Regulatory Polymorphism at Position -309 in PTPRCAP Is Associated with Susceptibility to Diffuse-type Gastric Cancer and Gene Expression1 
Neoplasia (New York, N.Y.)  2009;11(12):1340-1347.
PTPRCAP (CD45-AP) is a positive regulator of protein tyrosine phosphatase PTPRC (CD45), which activates Src family kinases implicated in tumorigenesis. Single-nucleotide polymorphism (SNP) rs869736 located at position -309 of the PTPRCAP promoter was associated with susceptibility to diffuse-type gastric cancer in the current case-control study. The minor-allele homozygote was significantly associated with a 2.5-fold increased susceptibility to diffuse-type gastric cancer (P = .0021, n = 252), but not to intestinal-type (P = .30, n = 178), versus the major-allele homozygote, when comparing unrelated Korean patients with healthy controls (n = 406). Nine other SNPs were in nearly perfect linkage disequilibrium (r2 ≥ 0.97) with this SNP, exhibiting the same association, and spread out for 26 kb on chromosome 11q13.1 covering RPS6KB2, PTPRCAP, CORO1B, and GPR152. Among the four genes, however, only PTPRCAP expression was affected by haplotypes of the 10 SNPs. Endogenous transcript levels of PTPRCAP were linearly correlated with copy numbers (0, 1, and 2) of the risk-haplotype (P = .0060) in 12 lymphoblastoid cells derived from blood samples, but those of the other three genes were not. Furthermore, the cancer-risk, minor-allele T of rs869736 increased both promoter activity and specific nuclear protein-binding affinity than the nonrisk, major-allele G in luciferase reporter and electrophoretic mobility shift assays, respectively. Accordingly, the minor allele of rs869736 in the PTPRCAP promoter is associated with increased susceptibility to diffuse-type gastric cancer by increasing PTPRCAP expression, possibly leading to activation of the oncogenic Src family kinases.
PMCID: PMC2794515  PMID: 20019842
8.  A functional variant in FcRH3, encoding Fc Receptor Homolog 3, is associated with rheumatoid arthritis and several autoimmunities 
Nature genetics  2005;37(5):478-485.
Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic etiology. Herein we identify a single-nucleotide polymorphism (SNP) in the promoter region of FcRH3, a member of the Fc receptor homolog family, that is associated with RA susceptibility (OR=2.15, P=0.00000085). This polymorphism alters the binding affinity of nuclear factor-κB and regulates FcRH3 expression. High FcRH3 expression on B-cells and augmented autoantibody production were observed in individuals with the disease-susceptible genotype. Associations were also found between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FcRH3 may thus play a pivotal role in autoimmunity.
PMCID: PMC1362949  PMID: 15838509
9.  Drosophila Med6 Is Required for Elevated Expression of a Large but Distinct Set of Developmentally Regulated Genes 
Molecular and Cellular Biology  2001;21(15):5242-5255.
Mediator is the evolutionarily conserved coactivator required for the integration and recruitment of diverse regulatory signals to basal transcription machinery. To elucidate the functions of metazoan Mediator, we isolated Drosophila melanogaster Med6 mutants. dMed6 is essential for viability and/or proliferation of most cells. dMed6 mutants failed to pupate and died in the third larval instar with severe proliferation defects in imaginal discs and other larval mitotic cells. cDNA microarray, quantitative reverse transcription-PCR, and in situ expression analyses of developmentally regulated genes in dMed6 mutants showed that transcriptional activation of many, but not all, genes was affected. Among the genes found to be affected were some that play a role in cell proliferation and metabolism. Therefore, dMed6 is required in most cells for transcriptional regulation of many genes important for diverse aspects of Drosophila development.
PMCID: PMC87248  PMID: 11438678
10.  DNA sequencing and genotyping by transcriptional synthesis of chain-terminated RNA ladders and MALDI-TOF mass spectrometry 
Nucleic Acids Research  2001;29(3):e11.
Sets of RNA ladders can be synthesized by transcription of a bacteriophage-encoded RNA polymerase using 3′-deoxynucleotides as chain terminators. These ladders can be used for sequencing of DNA. Using a nicked form of phage SP6 RNA polymerase in this study substantially enhanced yields of transcriptional sequencing ladders. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of chain-terminated RNA ladders allowed DNA sequence determination of up to 56 nt. It is also demonstrated that A→G and C→T variations in heterozygous and homozygous samples can be unambiguously identified by the mass spectrometric analysis. As a step towards single-tube sequencing reactions, α-thiotriphosphate nucleotide analogs were used to overcome problems caused by chain terminator-independent, premature termination and by the small mass difference between natural pyrimidine nucleotides.
PMCID: PMC30412  PMID: 11160913

Results 1-10 (10)