Informatics

 

We construct system-wide cellular regulatory network models composed of the regulation of gene expression, networked protein functions, and degradation in different cellular conditions. In our study, the concerted genetic or epigenetic regulation mechanisms in gene expression including the function of chromatin modifiers, transcription factors and small RNAs are integrated and modeled with the protein level regulation such as protein modification, interaction, localization and degradation. We, first, infer the regulatory relations among the genes with their meaningful patterns in sequence, expression, interaction, and biological function from the scattered data in literature and biological databases. Using the mathematical modeling and computational simulation, we characterize the possible regulatory models and the role of the component genes on the system.

 

 

 

 

 

 

 

 

 

 

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Reference

  1. Kimin Oh and Gwan-Su Yi (2016) "Prediction of scaffold proteins based on protein interaction and domain architecturesbmc bioinformatics, doi:10.1186/s12859-016-1079-5
  2. Kihoon Cha, Yi Li and Gwan-Su Yi (2016) "Discovering gene expression signatures responding to tyrosine kinase inhibitor treatment in chronic myeloid leukemia , BMC Medical Genomics, doi:10.1186/s12920-016-0194-5
  3. Kimin Oh, Taeho Hwang, Kihoon Cha, and Gwan-Su Yi (2015) "Disease association and inter-connectivity analysis of human brain specific co-expressed functional modules, Biological Research, doi:10.1186/s40659-015-0061-4
  4. Kihoon Cha, Kimin Oh, Taeho Hwang and Gwan-Su Yi (2015) "Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data", BMC Medical Informatics & Decision Making, DOI10.1186/1472-6947-15-S1-S7
  5. Yul Kim, Chiyong Kang, Bumki Min, Gwan-Su Yi (2015) "Detection and analysis of disease-associated single nucleotide polymorphism influencing post-translational modification", BMC Medical Genomics, DOI10.1186/1755-8794-8-S2-S7
  6. Jinki Kim and Gwan-Su Yi (2013) "RMOD: A Tool for Regulatory Motif Detection in Signaling Network" PLOS ONE 8:e68407
  7. Min-Sung Kim and Gwan-Su Yi (2013) "HMPAS: Human Membrane Protein Analysis System" Proteom Sci. vol. 11, S7
  8. Taegyun Yun and Gwan-Su Yi (2013) "Biclustering for the comprehensive search of correlated gene expression patterns using clustered seed expansion" BMC Genomics. 14:144
  9. Jinki Kim, and Gwan-Su Yi (2012) "PKMiner: a database for exploring type II polyketide synthase" BMC Microbiology 12:169
  10. Yul Kim, Bumki Min and Gwan-Su Yi (2012) "IDDI: integrated domain-domain interaction and protein interaction analysis system" Proteome Sci. 10(Suppl 1):S9
  11. Youngwoong Han, Hodong Lee, Jong C. Park and Gwan-Su Yi (2012) "E3Net: A system for exploring E3-mediated regulatory networks of cellular functions" Mol Cell Proteomics O111.014076
  12. Chiyong Kang and Gwan-Su Yi (2011) "Identification of ubiquitin/ubiquitin-like protein modification from tandem mass spectra with various PTMs." BMC Bioinformatics. Vol.12, Suppl 13:S8
  13. C-H. Sun, T. Hwang, K. Oh, G-S. Yi (2010) "DynaMod: Dynamic Functional Modularity Analysis" Nucleic Acids Res. 38:W103-W108
  14. T. Yun, T. Hwang, K. Cha and G-S. Yi (2010) "CLIC: Clustering analysis of Large microarray datasets with Individual dimension-based Clustering", Nucleic Acids Res. 38:W246-W253.
  15. T. Hwang, C-H. Sun, T. Yun and G-S. Yi (2010) "FiGS: a filter-based gene selection workbench for microarray data", BMC Bioinformatics 11:50.
  16. C-H. Sun, M-S. Kim, Y. Han, G-S. Yi (2009) "COFECO: Composite Function Annotation Enriched by Protein Complex Data" Nucleic Acids Res. 37:W350-W355.
  17. H. Lee, G-S. Yi, J.C. Park (2008) "E3Miner: a Text Mining Tool for Ubiquitin-Protein Ligases" Nucleic Acids Res. 36:W416-W422

 

 

Discovery

 

We identify significant functional modules and key regulators in the characterized regulatory models through association analyses with diseases or cellular function. At the first step, we estimate the significance of the models with condition specific association of SNPs, gene expression profiles and other relations of the members in the models using in-house or available tools. Furthermore, we validate the roles and relations of the candidate targets in the significant regulatory models with in vitro or model cell experiments. Finally, the effectiveness of the regulatory models and their key regulators on the specific cellular conditions are verified with the target cells or patient samples. Through this validation process, we pursue to discover the key regulators or the functional modules of the system controlling cellular functions or diseases, which can be suggested as systems biomarkers and engineering targets for cellular functions.

 

 

 

 

 

 

 

 

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Reference

  1. Young-Sun Lee, Jae Kwang Lee, Yeonju Bae, Bok-Soon Lee, Eunju Kim, Chang-Hoon Cho, Kanghyun Ryoo, Jiyun Yoo, Chul-Ho Kim, Gwan-Su Yi, Seok-Geun Lee, C. Justin Lee, Sang Soo Kang, Eun Mi Hwang, and Jae-Yong Park (2016) "Suppression of 14-3-3γ-mediated surface expression of ANO1 inhibits cancer progression of glioblastoma cells", Scientific Reports, doi:10.1038/srep26413
  2. Bumki Min, Jiwon Ryu, Seung-Wook Chi, Gwan-Su Yi (2015) "Ubiquitination-dependent degradation of p73 by the mitochondrial E3 ubiquitin ligase Hades", Biochemical and Biophysical Research Communications, doi:10.1016/j.bbrc.2015.09.163
  3. Jae-Sun Shin, Ji-Hyang Ha, Kwang-Hee Bae, Byoung Chul Park, Sung Goo Park, Dong-Hwa Lee, Kyoung-Seok Ryu, Gwan-Su Yi, Seung-Wook Chi (2015) "Structural Convergence of Unstructured p53 Family Transactivation Domains in MDM2 Recognition", Cell cycle, 14:4, 533-543 
  4. Dong-Hwa Lee, Ji-Hyang Ha, Yul Kim, Mi Jang, Sung Jean Park, Ho Sup Yoon, Eun-Hee Kim, Kwang-Hee Bae, Byoung Chul Park, Sung Goo Park, Gwan-Su Yi and Seung-Wook Chi (2014) “ A conserved Mechanism for Binding Of p53 DNA-Binding-Domain and Anti-Apoptoric Bcl-2 Family Proteins” Mol. & Cell vol. 37, 264
  5. Jangsup-Moon, Soon-Tae Lee, Jiye Choi, Keun-Hwa Jung, Hyunwoo Yang, Arshi Khalid, Jeong-Min Kim, Kyung-Il Park, Jung-Won Shin, Jae-Jun Ban, Gwan-Su Yi, Sang-Kun Lee, Daejong Jeon, Kon Chu (2014) “Unique Behavioral Characteristics and microRNA Signatures in a Drug Resistant Epilepsy Model” PLOS One vol. 9 e85617
  6. Chiyong Kang, Hyeji Yu and Gwan-Su Yi (2013) "Finding type 2 diabetes causal single nucleotide polymorphism combinations and functional modules from genome-wide association data" BMC Medical Informatics & Decision Making 13(suppl 1):S3
  7. Dong-Hwa Lee, Ji-Hyang Ha, Yul Kim, Kwang-Hee Bae, Jae Yong Park, Wan Sung Choi, Ho Sup Yoon, Sung Goo Park, Byoung Chul Park, Gwan-Su Yi and Seung-Wook Chi (2011) "Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy" Biochem Biophys Res Commun, Vol. 408, Issue 4, 541-547
  8. N. Kim, J.C. Yoo, J.Y. Han, E.M. Hwang, Y.S. Kim, E.Y. Jeong, C-H. Sun, G-S. Yi, G.S. Roh, H.J. Kim, S.S. Kang, G.J. Cho, J.Y. Park, W.S. Choi (2011) "Human nuclear clusterin mediates apoptosis by interacting with Bcl-XL through C-terminal coiled coil domain" J. Cell. Physiol. 227(3) 1157–1167
  9. J-Y. Park, E.M. Hwang, O. Yarishkin, J-H. Seo, E. Kim, J. Yoo, G-S. Yi, D-G. Kim, N. Park, C.M. Ha, J-h. La, D. Kang, J. Han, U. Oh and S-G. Hong (2008) "TRPM4b channel suppresses store-operated Ca2+ entry by a novel protein-protein interaction with the TRPC3 channel", Biochem. Biophys. Res. Commun. 368, 677-683
  10. B.M. Ku, Y.K. Lee, J.Y. Jeong, J. Mun, J.Y. Han, G.S. Roh, H.J. Kim, G.J. Cho, W.S. Choi, G-S. Yi, S.S. Kang (2007) "Ethanol-induced oxidative stress is mediated by p38 pathway in mouse hippocampal cells", Neuroscience Letters 419, 64
  11. A. Ayed, F.A. Mulder, G-S. Yi, Y. Lu, L.E. Kay, C.H. Arrowsmith (2001) "Latent and Active p53 are Identical in Conformation" Nature Structural Biology 8(9), 756-760
  12. C.B. Park, K-S. Yi, K Matsuzaki, M.S. Kim, S.C. Kim (2000) "Structure-activity analysis of buforin II, a histone H2A-derived antimicrobial peptide: The proline hinge is responsible for the cell-penetrationing ability of buforin II" Proc. Natl. Acad. Sci. U.S.A. 97(15), 8245-8250

 

 

Engineering

 

The validated key regulators and their associated functional modules are engineered to manipulate cellular functions based on the comprehensive information acquired from the informatics and discovery processes. We target the key regulator proteins of the validated model and change their molecular activities or interaction properties based on the structural implication of protein in the level of individual residues, motifs, domains, and possible PTMs. We will also try to engineer the genomic structure and protein biosynthesis process in the cell to generate alternative forms of proteins efficiently. Our comprehensive understanding of the regulatory networks of cellular functions and the structural details of target proteins will support to construct more reasonable synthetic models that overcome many huddles that current synthetic biology faces in practical implementation. Especially, we are interested in multi-functional and multi-targeting proteins such as scaffold proteins and their targeting function modules as our prior engineering targets. Reconstructed antibodies are other possible targets. The engineered proteins or their interacting peptides designed in this comprehensive process can be used in detecting or manipulating the cellular functions including cellular pathways or regulation circuitry with high fidelity and flexibility. The results will provide more refined solutions in diagnosis and treatment of disease, and cellular function engineering in many biomedical application fields.

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Reference

 

  1. Dokyun Na, Sunjae Lee, Gwan-Su Yi and Doheon Lee (2011) "Synthetic inter-species cooperation of host and virus for targeted genetic evolution" Journal of Biotechnology. Vol. 153, Issue 1-2, 35-41
  2. E. Kim, E.M. Hwang, O. Yarishkin, J.C. Yoo, D. Kim, N. Park, M. Cho, Y. S. Lee, C-H. Sun, G-S. Yi, J. Yoo, D. Kang, J. Han, S-G. Hong and J-Y. Park (2010) "Enhancement of trek1 channel surface expression by protein-protein interaction with beta-cop", Biochem. Biophys. Res. Commun. 395, 244-250
  3. S-W. Chi, J. Kim, G-S. Yi, H.J. Hong, S.E. Ryu (2009) "Broadly neutralizing anti-HBV antibody binds to non-epitope regions of preS1", FEBS Lett. 583, Issue 18, 3095-3100
  4. Jongmin Kim, Jong Man Kim, Seok Joo Hong, Jun Ho Park, Sun Young Park, Taeho Hwang, Gwan-Su Yi, Seong Hwan Kim, Eun Yoon Cho, Jae-Won Joh, Jin Young Park, Dae Shick Kim (2009) "Increased Expression of Autophagy protein Beclin1 and LC3 in High-grade Hepatocellular Carcinoma and Metastatic Carcinoma", Biochip Journal, Vol. 3, No. 4, 316-325.
  5. E. Bochkareva, L. Kaustov, A. Ayed, G-S. Yi, Y. Lu, A. Pineda-Lucena, J.C. Liao, A.L. Okorokov, J. Milner, C.H. Arrowsmith and A. Bochkarev (2005) "Single-stranded DNA mimicry in the p53 transactivation domain interaction with replication protein A" Proc. Natl. Acad. Sci. U.S.A. 102 (43), 15412-15417
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