Kiejung Park

MapsiDB: an integrated web database for type I polyketide synthases

Polyketides have diverse biological activities, including pharmacological functions such as antibiotic, antitumor and agrochemical properties. They are biosynthesized from short carboxylic acid precursors by polyketide synthases (PKSs). As natural polyketide products include many clinically important drugs and the volume of data on polyketides is rapidly increasing, the development of a database system to manage polyketide data is essential. MapsiDB is an integrated web database formulated to contain data on type I polyketides and their PKSs, including domain and module composition and related genome information. Data on polyketides were collected from journals and online resources and processed with analysis programs. Web interfaces were utilized to construct and to access this database, allowing polyketide researchers to add their data to this database and to use it easily.

Genetic factors underlying discordance in chromatin accessibility between monozygotic twins

BackgroundOpen chromatin is implicated in regulatory processes; thus, variations in chromatin structure may contribute to variations in gene expression and other phenotypes. In this work, we perform targeted deep sequencing for open chromatin, and array-based genotyping across the genomes of 72 monozygotic twins to identify genetic factors regulating co-twin discordance in chromatin accessibility.ResultsWe show that somatic mutations cause chromatin discordance mainly via the disruption of transcription factor binding sites. Structural changes in DNA due to C:G to A:T transversions are under purifying selection due to a strong impact on chromatin accessibility. We show that CpGs whose methylation is specifically regulated during cellular differentiation appear to be protected from high mutation rates of 5′-methylcytosines, suggesting that the spectrum of CpG variations may be shaped fully at the developmental level but not through natural selection. Based on the association mapping of within-pair chromatin differences, we search for cases in which twin siblings with a particular genotype had chromatin discordance at the relevant locus. We identify 1,325 chromatin sites that are differentially accessible, depending on the genotype of a nearby locus, suggesting that epigenetic differences can control regulatory variations via interactions with genetic factors. Poised promoters present high levels of chromatin discordance in association with either somatic mutations or genetic-epigenetic interactions.ConclusionOur observations illustrate how somatic mutations and genetic polymorphisms may contribute to regulatory, and ultimately phenotypic, discordance.

KGVDB: a population-based genomic map of CNVs tagged by SNPs in Koreans

SUMMARY Despite a growing interest in a correlation between copy number variations (CNVs) and flanking single nucleotide polymorphisms, few databases provide such information. In particular, most information on CNV available so far was obtained in Caucasian and Yoruba populations, and little is known about CNV in Asian populations. This article presents a database that provides CNV regions tagged by single nucleotide polymorphisms in about 4700 Koreans, which were detected under strict quality control, manually curated and experimentally validated. AVAILABILITY KGVDB is freely available for non-commercial use at http://biomi.cdc.go.kr/KGVDB. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Increased Expression of Interferon Signaling Genes in the Bone Marrow Microenvironment of Myelodysplastic Syndromes

Introduction The bone marrow (BM) microenvironment plays an important role in the pathogenesis of myelodysplastic syndromes (MDS) through a reciprocal interaction with resident BM hematopoietic cells. We investigated the differences between BM mesenchymal stromal cells (MSCs) in MDS and normal individuals and identified genes involved in such differences. Materials and Methods BM-derived MSCs from 7 MDS patients (3 RCMD, 3 RAEB-1, and 1 RAEB-2) and 7 controls were cultured. Global gene expression was analyzed using a microarray. Result We found 314 differentially expressed genes (DEGs) in RCMD vs. control, 68 in RAEB vs. control, and 51 in RAEB vs. RCMD. All comparisons were clearly separated from one another by hierarchical clustering. The overall similarity between differential expression signatures from the RCMD vs. control comparison and the RAEB vs. control comparison was highly significant (p = 0), which indicates a common transcriptomic response in these two MDS subtypes. RCMD and RAEB simultaneously showed an up-regulation of interferon alpha/beta signaling and the ISG15 antiviral mechanism, and a significant fraction of the RAEB vs. control DEGs were also putative targets of transcription factors IRF and ICSBP. Pathways that involved RNA polymerases I and III and mitochondrial transcription were down-regulated in RAEB compared to RCMD. Conclusion Gene expression in the MDS BM microenvironment was different from that in normal BM and exhibited altered expression according to disease progression. The present study provides genetic evidence that inflammation and immune dysregulation responses that involve the interferon signaling pathway in the BM microenvironment are associated with MDS pathogenesis, which suggests BM MSCs as a possible therapeutic target in MDS.

Expression Signature Defined by FOXM1–CCNB1 Activation Predicts Disease Recurrence in Non–Muscle-Invasive Bladder Cancer

Purpose: Although standard treatment with transurethral resection and intravesical therapy (IVT) is known to be effective to address the clinical behavior of non–muscle-invasive bladder cancer (NMIBC), many patients fail to respond to the treatment and frequently experience disease recurrence. Here, we aim to identify a prognostic molecular signature that predicts the NMIBC heterogeneity and response to IVT. Experimental Design: We analyzed the genomic profiles of 102 patients with NMIBC to identify a signature associated with disease recurrence. The validity of the signature was verified in three independent patient cohorts (n = 658). Various statistical methods, including a leave-one-out cross-validation and multivariate Cox regression analyses, were applied to identify a signature. We confirmed an association between the signature and tumor aggressiveness with experimental assays using bladder cancer cell lines. Results: Gene expression profiling in 102 patients with NMIBC identified a CCNB1 signature associated with disease recurrence, which was validated in another three independent cohorts of 658 patients. The CCNB1 signature was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade [HR, 2.93; 95% confidence intervals (CI), 1.302–6.594; P = 0.009]. The subset analysis also revealed that the signature could identify patients who would benefit from IVT. Finally, gene network analyses and experimental assays indicated that NMIBC recurrence could be mediated by FOXM1–CCNB1–Fanconi anemia pathways. Conclusions: The CCNB1 signature represents a promising diagnostic tool to identify patients with NMIBC who have a high risk of recurrence and to predict response to IVT. Clin Cancer Res; 20(12); 3233–43. ©2014 AACR.

Global transcription network incorporating distal regulator binding reveals selective cooperation of cancer drivers and risk genes.

Global network modeling of distal regulatory interactions is essential in understanding the overall architecture of gene expression programs. Here, we developed a Bayesian probabilistic model and computational method for global causal network construction with breast cancer as a model. Whereas physical regulator binding was well supported by gene expression causality in general, distal elements in intragenic regions or loci distant from the target gene exhibited particularly strong functional effects. Modeling the action of long-range enhancers was critical in recovering true biological interactions with increased coverage and specificity overall and unraveling regulatory complexity underlying tumor subclasses and drug responses in particular. Transcriptional cancer drivers and risk genes were discovered based on the network analysis of somatic and genetic cancer-related DNA variants. Notably, we observed that the risk genes were functionally downstream of the cancer drivers and were selectively susceptible to network perturbation by tumorigenic changes in their upstream drivers. Furthermore, cancer risk alleles tended to increase the susceptibility of the transcription of their associated genes. These findings suggest that transcriptional cancer drivers selectively induce a combinatorial misregulation of downstream risk genes, and that genetic risk factors, mostly residing in distal regulatory regions, increase transcriptional susceptibility to upstream cancer-driving somatic changes.

BioStore: A Repository System for Registering and Distributing Public Biology Databases

Abstract Although abundant biology data have been accumulated in public biology databases, such as GenBank and PIR, few easy-interface services are provided for users to ac-cess or update them. We have developed a system, named BioStore, that is composed of several programs to aid users to not only access public data but also share their own data easily. The service can be used for maintaining a local database as a repository of raw data files of several public databases and distributing the da-ta files to other users. Currently, BioStore manipulates major bio-databases and will expand to include more databases and more useful interfaces.Availability: This system is available from http://www. ccbb.re.kr/biostoreKeywords: BioStore, FTP, GenBank, repository Introduction Biology data, especially DNA and protein sequence da-ta, are very rapidly increasing. Most data have been submitted to major bioinformatics databases, such as GenBank (Benson et al., 1994), PIR (McGarvey et al., 2000), and PDB (Berman, 2000), which are distributed via FTP services to a lot of bioinformatics sites and users. As more and more bio-databases (Jeon et al., 2005; Kim et al., 2008) are constructed and a large amount of data files is kept in each database, most bi-ology researchers have difficulty in searching for in-formation and in sharing their own data with others. CCBB (Center for Computational Biology and Bioin-formatics) of the Korea Institute of Science and Technol-ogy Information has been providing an FTP server and analysis services for major bio-databases. We have de-veloped BioStore as a repository system by implement-ing a few programs to register user data, including pub-lic bio-data at CCBB. Researchers can easily register their own data with BioStore through the system to share them with others.

Genovar: a detection and visualization tool for genomic variants

BackgroundAlong with single nucleotide polymorphisms (SNPs), copy number variation (CNV) is considered an important source of genetic variation associated with disease susceptibility. Despite the importance of CNV, the tools currently available for its analysis often produce false positive results due to limitations such as low resolution of array platforms, platform specificity, and the type of CNV. To resolve this problem, spurious signals must be separated from true signals by visual inspection. None of the previously reported CNV analysis tools support this function and the simultaneous visualization of comparative genomic hybridization arrays (aCGH) and sequence alignment. The purpose of the present study was to develop a useful program for the efficient detection and visualization of CNV regions that enables the manual exclusion of erroneous signals.ResultsA JAVA-based stand-alone program called Genovar was developed. To ascertain whether a detected CNV region is a novel variant, Genovar compares the detected CNV regions with previously reported CNV regions using the Database of Genomic Variants (DGV, http://projects.tcag.ca/variation) and the Single Nucleotide Polymorphism Database (dbSNP). The current version of Genovar is capable of visualizing genomic data from sources such as the aCGH data file and sequence alignment format files.ConclusionsGenovar is freely accessible and provides a user-friendly graphic user interface (GUI) to facilitate the detection of CNV regions. The program also provides comprehensive information to help in the elimination of spurious signals by visual inspection, making Genovar a valuable tool for reducing false positive CNV results. Availability: http://genovar.sourceforge.net/.

A Bio-database Management System for the Monitoring and Automatic FTP of Public Databases

Many bioinformatics sites have managed local bio-databases, including major databases such as GenBank and PIR with update load. We have developed several programs to monitor the update status of these databases and to FTP them automatically. These programs can be used for maintaining local bio-databases as recent versions and providing up-to-date databases through FTP sites. Currently, the program serves major bio-databases and will extend to accommodate many more bio-databases.

Computational Approach for Biosynthetic Engineering of Post-PKS Tailoring Enzymes

Abstract Compounds of polyketide origin possess a wealth of pharmacological effects, including antibacterial, anti-fungal, antiparasitic, anticancer and immunosuppressive activities. Many of these compounds and their semi- synthetic derivatives are used today in the clinic. Most of the gene clusters encoding commercially important drugs have also been cloned and sequenced and their biosynthetic mechanisms studied in great detail. The area of biosynthetic engineering of the enzymes involved in polyketide biosynthesis has recently advanced and been transferred into the industrial arena. In this work, we introduce a computational system to provide the user with a wealth of information that can be utilized for biosynthetic engineering of enzymes involved in post- PKS tailoring steps. Post-PKS tailoring steps are neces-sary to add functional groups essential for the biological activity and are therefore important in polyketide biosyn-thesis.Availability: The trial version of this system is available via WWW at http://sm.hacklib.com/.Keywords: pharmacological effects, gene clusters, bio-synthetic engineering, post-PKS tailoring step