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Search Results: 1 - 10 of 218 matches for " Tatsuhiko Tsunoda "
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MotifCombinator: a web-based tool to search for combinations of cis-regulatory motifs
Mamoru Kato, Tatsuhiko Tsunoda
BMC Bioinformatics , 2007, DOI: 10.1186/1471-2105-8-100
Abstract: We here introduced MotifCombinator, an online tool with a user-friendly interface, to systematically search for combinations composed of any number of motifs based on regression methods. The tool utilizes well-known regression methods (the multivariate linear regression, the multivariate adaptive regression spline or MARS, and the multivariate logistic regression method) for this purpose, and uses the genetic algorithm to search for combinations composed of any desired number of motifs. The visualization systems in this tool help users to intuitively grasp the process of the combination search, and the backup system allows users to easily stop and restart calculations that are expected to require large computational time. This tool also provides preparatory steps needed for systematic combination search – i.e., selecting single motifs to constitute combinations and cutting out redundant similar motifs based on clustering analysis.MotifCombinator helps users to systematically search for motif combinations that play an important role in gene expression as measured by microarrays.Gene expression in eukaryotes is controlled by combinatorial regulation of transcription factors and cis-regulatory elements. Many types of transcription factors are bound to their respective regulatory DNA elements, and the interactions between the factors and elements control the gene expression. Molecular experiments can identify several binding sites for selected transcription factors, but they are too laborious and time-consuming to be applied to large-scale studies. Computational methods are thus required for processing genomic data to reveal the combinatorial regulation on a genomic scale.Recently, some computational methods have been developed to detect combinations of patterns (motifs) of cis-regulatory elements. They process data of upstream sequences selected from genomic sequences, as well as data of either expression levels measured by DNA microarrays or binding information given
hzAnalyzer: detection, quantification, and visualization of contiguous homozygosity in high-density genotyping datasets
Todd A Johnson, Yoshihito Niimura, Hiroshi Tanaka, Yusuke Nakamura, Tatsuhiko Tsunoda
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-3-r21
Abstract: Homozygosity represents a simple but important concept for exploring human population history, the structure of human genetic variation, and their intersection with human disease. At its most basic level, homozygosity means that, for a particular locus, the two copies that are inherited from an individual's parents both have the same allelic value and are identical-by-state. However, if the two homologues originate from the same ancestor in their genealogic histories, then the two copies can be described as being identical-by-descent and the locus referred to as autozygous [1]. While autozygosity stems from recent relatedness between an individual's parents, shared ancestry from the much more distant past can nevertheless result in portions of any two homologous chromosomes being homozygous by descent, reflecting background relatedness within a population [2]. Researchers need to integrate information across multiple contiguous homozygous SNPs in an individual's genome to detect such homozygous segments, which, by their very nature, represent known haplotypes within otherwise phase-unknown datasets. As such, they potentially represent a higher-level abstraction of information than that which can be obtained from analysis of just single SNPs. Since this has potential for identifying shared haplotypes that harbor disease variants that escape current single-marker statistical tests, the field would benefit from additional software tools and methodologies for strengthening our understanding of the distribution and variation of homozygous segments/contiguous homozygosity within human population samples.Early attempts to understand the contribution of contiguous homozygosity to the structure of genetic variation in modern human populations identified regions of increased homozygous genotypes in individuals that likely represented autozygosity [3]. However, due to technological limitations at the time, their micro-satellite-based scan limited resolution of segments to thos
Linkage disequilibrium of evolutionarily conserved regions in the human genome
Mamoru Kato, Akihiro Sekine, Yozo Ohnishi, Todd A Johnson, Toshihiro Tanaka, Yusuke Nakamura, Tatsuhiko Tsunoda
BMC Genomics , 2006, DOI: 10.1186/1471-2164-7-326
Abstract: Unexpectedly, we observed that LD was significantly weaker in conserved regions than in non-conserved regions. To investigate why, we examined sequence features that may distort the relationship between LD and conserved regions. We found that interspersed repeats, and not other sequence features, were associated with the weak LD tendency in conserved regions. To appropriately understand the relationship between LD and conserved regions, we removed the effect of repetitive elements and found that the high degree of sequence conservation was strongly associated with strong LD in coding regions but not with that in non-coding regions.Our work demonstrates that the degree of sequence conservation does not simply increase LD as predicted by the hypothesis. Rather, it implies that purifying selection changes the polymorphic patterns of coding sequences but has little influence on the patterns of functional units such as regulatory elements present in non-coding regions, since the former are generally restricted by the constraint of maintaining a functional protein product across multiple exons while the latter may exist more as individually isolated units.Linkage disequilibrium (LD) is non-random association between alleles at different loci and helps us to reconstruct the genetic history of human populations and to improve our understanding of the biological processes of recombination and natural selection [1]. LD also helps association studies to identify haplotypes that are linked to disease-causing variations. Early studies of LD focused on small sets of genes, such as the HLA genes [2] or the growth hormone gene cluster [3]. Recently, large-scale genotyping studies [1,4-6] have investigated the genomic patterns of LD in the human genome and have found considerable variation in its values, even for SNP pairs that are separated by identical physical distances. Some studies have tried to associate this variation with sequence features existing in the genome and found th
A Genome-Wide Association Study of Nephrolithiasis in the Japanese Population Identifies Novel Susceptible Loci at 5q35.3, 7p14.3, and 13q14.1
Yuji Urabe,Chizu Tanikawa,Atsushi Takahashi,Yukinori Okada,Takashi Morizono,Tatsuhiko Tsunoda,Naoyuki Kamatani,Kenjiro Kohri,Kazuaki Chayama,Michiaki Kubo,Yusuke Nakamura,Koichi Matsuda
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002541
Abstract: Nephrolithiasis is a common nephrologic disorder with complex etiology. To identify the genetic factor(s) for nephrolithiasis, we conducted a three-stage genome-wide association study (GWAS) using a total of 5,892 nephrolithiasis cases and 17,809 controls of Japanese origin. Here we found three novel loci for nephrolithiasis: RGS14-SLC34A1-PFN3-F12 on 5q35.3 (rs11746443; P = 8.51×10?12, odds ratio (OR) = 1.19), INMT-FAM188B-AQP1 on 7p14.3 (rs1000597; P = 2.16×10?14, OR = 1.22), and DGKH on 13q14.1 (rs4142110; P = 4.62×10?9, OR = 1.14). Subsequent analyses in 21,842 Japanese subjects revealed the association of SNP rs11746443 with the reduction of estimated glomerular filtration rate (eGFR) (P = 6.54×10?8), suggesting a crucial role for this variation in renal function. Our findings elucidated the significance of genetic variations for the pathogenesis of nephrolithiasis.
Engineered Monoclonal Antibody with Novel Antigen-Sweeping Activity In Vivo
Tomoyuki Igawa, Atsuhiko Maeda, Kenta Haraya, Tatsuhiko Tachibana, Yuki Iwayanagi, Futa Mimoto, Yoshinobu Higuchi, Shinya Ishii, Shigero Tamba, Naoka Hironiwa, Kozue Nagano, Tetsuya Wakabayashi, Hiroyuki Tsunoda, Kunihiro Hattori
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063236
Abstract: Monoclonal antibodies are widely used to target disease-related antigens. However, because conventional antibody binds to the antigen but cannot eliminate the antigen from plasma, and rather increases the plasma antigen concentration by reducing the clearance of the antigen, some clinically important antigens are still difficult to target with monoclonal antibodies because of the huge dosages required. While conventional antibody can only bind to the antigen, some natural endocytic receptors not only bind to the ligands but also continuously eliminate them from plasma by pH-dependent dissociation of the ligands within the acidic endosome and subsequent receptor recycling to the cell surface. Here, we demonstrate that an engineered antibody, named sweeping antibody, having both pH-dependent antigen binding (to mimic the receptor-ligand interaction) and increased binding to cell surface neonatal Fc receptor (FcRn) at neutral pH (to mimic the cell-bound form of the receptor), selectively eliminated the antigen from plasma. With this novel antigen-sweeping activity, antibody without in vitro neutralizing activity exerted in vivo efficacy by directly eliminating the antigen from plasma. Moreover, conversion of conventional antibody with in vitro neutralizing activity into sweeping antibody further potentiated the in vivo efficacy. Depending on the binding affinity to FcRn at neutral pH, sweeping antibody reduced antigen concentration 50- to 1000-fold compared to conventional antibody. Thereby, sweeping antibody antagonized excess amounts of antigen in plasma against which conventional antibody was completely ineffective, and could afford marked reduction of dosage to a level that conventional antibody can never achieve. Thus, the novel mode of action of sweeping antibody provides potential advantages over conventional antibody and may allow access to the target antigens which were previously undruggable by conventional antibody.
The Construction of Risk Prediction Models Using GWAS Data and Its Application to a Type 2 Diabetes Prospective Cohort
Daichi Shigemizu, Testuo Abe, Takashi Morizono, Todd A. Johnson, Keith A. Boroevich, Yoichiro Hirakawa, Toshiharu Ninomiya, Yutaka Kiyohara, Michiaki Kubo, Yusuke Nakamura, Shiro Maeda, Tatsuhiko Tsunoda
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092549
Abstract: Recent genome-wide association studies (GWAS) have identified several novel single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D). Various models using clinical and/or genetic risk factors have been developed for T2D risk prediction. However, analysis considering algorithms for genetic risk factor detection and regression methods for model construction in combination with interactions of risk factors has not been investigated. Here, using genotype data of 7,360 Japanese individuals, we investigated risk prediction models, considering the algorithms, regression methods and interactions. The best model identified was based on a Bayes factor approach and the lasso method. Using nine SNPs and clinical factors, this method achieved an area under a receiver operating characteristic curve (AUC) of 0.8057 on an independent test set. With the addition of a pair of interaction factors, the model was further improved (p-value 0.0011, AUC 0.8085). Application of our model to prospective cohort data showed significantly better outcome in disease-free survival, according to the log-rank trend test comparing Kaplan-Meier survival curves (). While the major contribution was from clinical factors rather than the genetic factors, consideration of genetic risk factors contributed to an observable, though small, increase in predictive ability. This is the first report to apply risk prediction models constructed from GWAS data to a T2D prospective cohort. Our study shows our model to be effective in prospective prediction and has the potential to contribute to practical clinical use in T2D.
Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s
Michele Carbone?,Erin G. Flores?,Mitsuru Emi?,Todd A. Johnson?,Tatsuhiko Tsunoda,Dusty Behner?,Harriet Hoffman?,Mary Hesdorffer?,Masaki Nasu?,Andrea Napolitano
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005633
Abstract: We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).
Functional Variants in NFKBIE and RTKN2 Involved in Activation of the NF-κB Pathway Are Associated with Rheumatoid Arthritis in Japanese
Keiko Myouzen,Yuta Kochi ,Yukinori Okada,Chikashi Terao,Akari Suzuki,Katsunori Ikari,Tatsuhiko Tsunoda,Atsushi Takahashi,Michiaki Kubo,Atsuo Taniguchi,Fumihiko Matsuda,Koichiro Ohmura,Shigeki Momohara,Tsuneyo Mimori,Hisashi Yamanaka,Naoyuki Kamatani,Ryo Yamada,Yusuke Nakamura,Kazuhiko Yamamoto
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002949
Abstract: Rheumatoid arthritis is an autoimmune disease with a complex etiology, leading to inflammation of synovial tissue and joint destruction. Through a genome-wide association study (GWAS) and two replication studies in the Japanese population (7,907 cases and 35,362 controls), we identified two gene loci associated with rheumatoid arthritis susceptibility (NFKBIE at 6p21.1, rs2233434, odds ratio (OR) = 1.20, P = 1.3×10?15; RTKN2 at 10q21.2, rs3125734, OR = 1.20, P = 4.6×10?9). In addition to two functional non-synonymous SNPs in NFKBIE, we identified candidate causal SNPs with regulatory potential in NFKBIE and RTKN2 gene regions by integrating in silico analysis using public genome databases and subsequent in vitro analysis. Both of these genes are known to regulate the NF-κB pathway, and the risk alleles of the genes were implicated in the enhancement of NF-κB activity in our analyses. These results suggest that the NF-κB pathway plays a role in pathogenesis and would be a rational target for treatment of rheumatoid arthritis.
Hepatitis C Virus Infection Suppresses the Interferon Response in the Liver of the Human Hepatocyte Chimeric Mouse
Masataka Tsuge, Yoshifumi Fujimoto, Nobuhiko Hiraga, Yizhou Zhang, Mayu Ohnishi, Tomohiko Kohno, Hiromi Abe, Daiki Miki, Michio Imamura, Shoichi Takahashi, Hidenori Ochi, C. Nelson Hayes, Fuyuki Miya, Tatsuhiko Tsunoda, Kazuaki Chayama
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023856
Abstract: Background and Aims Recent studies indicate that hepatitis C virus (HCV) can modulate the expression of various genes including those involved in interferon signaling, and up-regulation of interferon-stimulated genes by HCV was reported to be strongly associated with treatment outcome. To expand our understanding of the molecular mechanism underlying treatment resistance, we analyzed the direct effects of interferon and/or HCV infection under immunodeficient conditions using cDNA microarray analysis of human hepatocyte chimeric mice. Methods Human serum containing HCV genotype 1b was injected into human hepatocyte chimeric mice. IFN-α was administered 8 weeks after inoculation, and 6 hours later human hepatocytes in the mouse livers were collected for microarray analysis. Results HCV infection induced a more than 3-fold change in the expression of 181 genes, especially genes related to Organismal Injury and Abnormalities, such as fibrosis or injury of the liver (P = 5.90E-16 ~ 3.66E-03). IFN administration induced more than 3-fold up-regulation in the expression of 152 genes. Marked induction was observed in the anti-fibrotic chemokines such as CXCL9, suggesting that IFN treatment might lead not only to HCV eradication but also prevention and repair of liver fibrosis. HCV infection appeared to suppress interferon signaling via significant reduction in interferon-induced gene expression in several genes of the IFN signaling pathway, including Mx1, STAT1, and several members of the CXCL and IFI families (P = 6.0E-12). Genes associated with Antimicrobial Response and Inflammatory Response were also significantly repressed (P = 5.22×10?10 ~ 1.95×10?2). Conclusions These results provide molecular insights into possible mechanisms used by HCV to evade innate immune responses, as well as novel therapeutic targets and a potential new indication for interferon therapy.
Overexpression of the JmjC histone demethylase KDM5B in human carcinogenesis: involvement in the proliferation of cancer cells through the E2F/RB pathway
Shinya Hayami, Masanori Yoshimatsu, Abhimanyu Veerakumarasivam, Motoko Unoki, Yukiko Iwai, Tatsuhiko Tsunoda, Helen I Field, John D Kelly, David E Neal, Hiroki Yamaue, Bruce AJ Ponder, Yusuke Nakamura, Ryuji Hamamoto
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-59
Abstract: Quantitative RT-PCR analysis confirmed that expression levels of KDM5B are significantly higher in human bladder cancer tissues than in their corresponding non-neoplastic bladder tissues (P < 0.0001). The expression profile analysis of clinical tissues also revealed up-regulation of KDM5B in various kinds of malignancies. Transfection of KDM5B-specific siRNA into various bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells and increased the number of cells in sub-G1 phase. Microarray expression analysis indicated that E2F1 and E2F2 are downstream genes in the KDM5B pathway.Inhibition of KDM5B may affect apoptosis and reduce growth of cancer cells. Further studies will explore the pan-cancer therapeutic potential of KDM5B inhibition.Histone methylation plays an important dynamic role in regulating chromatin structure. Precise coordination and organization of open and closed chromatins are crucial for normal cellular processes such as DNA replication, repair, recombination and transcription. Until recently, histone methylation was considered to be a static modification, but the identification of histone demethylases has revealed that this modification is dynamically regulated [1,2]. Histone demethylases regulate not only the modification itself but also its extended function, by antagonizing the binding of effector proteins to modified chromatin. This is exemplified by JHDM3A/JMJD2A, which displaces HP1 from chromatin by demethylating the H3K9 methylation and thereby preventing the spread of H3K9 methylation to the surrounding chromatin by HP1 [3,4]. A highly-conserved family of proteins containing the JmjC domain was recently characterized to possess a histone demethylase activity [5]. Despite a large body of information for the prominent role of histone demethylases in transcriptional regulation, their physiological function, and their involvement in human disease is still not well-understood.We previously reported that SMYD3
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