研究員 / 物理與資訊基因體學專題中心執行長

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EDUCATION AND POSITIONS HELD:

• B.S., Department of Botany, National Taiwan University, 1979
• Ph.D., State University of New York at Buffalo, 1986
• Postdoctoral Fellow, California Institute of Technology, 1987-1991
• Assistant Professor, Ohio State University, 1992-1998
• Associate Professor, Ohio State University, 1999-2006
• Associate Professor, Genomics Research Center, Academia Sinica, 2007-2019
• Deputy Director, Genomics Research Center, Academia Sinica, 2016-2019
• Professor, Genomics Research Center, Academia Sinica, 2019-present
• Acting Director, Genomics Research Center, Academia Sinica, 2022-2023
• Division director of the Physical and Computational Genomics division, Genomics Research Center, Academia Sinica, 2023-present

HONORS:

• Dean's Award for Classroom Teaching, College of Biological Sciences, Ohio State University
• Outstanding teacher, College of Biological Sciences, Ohio State University
• Merck Sharp & Dohme Laboratories Postdoctoral Fellowship, California Institute of Technology
• Genetic Graduate Group Predoctoral Fellowship, State University of New York at Buffalo

RESEARCH INTERESTS:

RNA Metabolism Mediated by DExD/H-box RNA Helicases

Example of a Bypass Genetics ScreenWe have been studying the functions of the ubiquitous DExD/H-box proteins, which are often referred to as RNA helicases or RNA unwindases, in the budding yeast Saccharomyces cerevisiae and other organisms. These proteins are involved in essentially all RNA-related biological processes such as mRNA splicing, ribosomal biogenesis, mRNA export, translation, and RNA turnover. We have systematically examined the roles of a number of DExD/H-box proteins in yeast using a combination of genetic, molecular biological, biochemical, bioinformatic, and cell biological approaches. These studies allowed us to define the functions of Dbp3p (60S ribosomal subunit biogenesis), Dbp5p (mRNA export), Ded1p (translation initiation), Dhh1p (RNA turnover), and Prp28p (pre-mRNA splicing). Our study on Prp28p revealed that it controls the dissociation of U1 snRNP from the 5' splice site. This work bears significant ramifications and helps to usher in a notable paradigm shift in the field. It is now believed that the in vivo targets of DExD/H-box proteins are likely to be RNP complexes, rather than the RNA duplexes per se. Thus, DExD/H-box proteins function most likely as “RNPases” to “re-configure” various RNP complexes during and upon their transcriptional birth, their processing and export to cytoplasm for translation, and their ultimate demise by RNA turnover. In short, DExD/H-box proteins play key roles in governing the itinerary and functionality of the genetic information packages, from cradle to grave. Last, but not least, we are also exploring the possibility that one of the cellular DExD/H-box proteins is required for hepatitis C virus (HCV) replication. Studies of this DExD/H-box protein may provide a critical handle to understand how HCV replicates in the cell.

Genome-wide mRNA Splicing

By its nature and position in the gene expression pathway, splicing plays a key role in interpreting the embedded genomic information and does so under developmental and environmental influence. We have used splicing-specific microarrays to dissect how different processes, such as transcription, splicing, mRNA export, mRNA turnover, and translation, are coordinated.

A Genome-wide Bypass Genetics Screen for Yeast Essential Genes

Research done over the past few years in our lab has uncovered that a number of the so-called “essential” genes can in fact be eliminated, provided that specific “bypass” mutations are in place. Cloning the genes corresponding to the bypass mutations proved to yield rich and penetrating insights into the mechanistic role of the essential gene in question. We have therefore undertaken a systematic genome-wide screen for bypass mutations. Bypassing an essential gene is an extraordinary event and, as such, studies of bypass mutations virtually guarantee the discovery of novel and exciting biology. In this uncharted territory, we hope to uncover novel gene functions, genetic networks, as well as the underlying logic of genome evolution and organization.

SELECTED PUBLICATIONS:

• Antika, T. R., Lee, Y.-H., Lo, Y.-T., Yeh, C.-S., Yeh, F.-L., 「Chang, T.-H.」, Wang, T.-L., and Wang, C.-C.*, 2022, “Human Thg1 displays tRNA-inducible GTPase activity”, NUCLEIC ACIDS RESEARCH, 50, 10015-10025. (SCIE)
• Yeh, F.-L., Chang, S.-L., Ahmed, G. R., Liu, H.-I, Tung, L., Yeh, C.-S., Lanier, L. S., Maeder, C., Lin, C.-M., Tsai, S.-C., Hsiao, W.-Y., Chang, W.-H., and Chang, T.-H.*, 2021, “Activation of Prp28 ATPase by phosphorylated Npl3 at a critical step of spliceosome remodeling”, NATURE COMMUNICATIONS, 12, 3082. (SCIE)
• Tsai, N.-C., Hsu, T.-S., Kuo, S.-C., Kao, C.-T., Hung, T.-H., Lin, D.-G., Yeh, C.-S., Chu, C.-C., Lin, J.-S., Lin, H.-H.; Ko, C.-Y., Chang, T.-H.*, Su, J.-C.*, and Lin, Y.-C.*, 2021, “Large-scale data analysis for robotic yeast one-hybrid platforms and multi-disciplinary studies using GateMultiplex”, BMC Biology, 19, 214. (SCIE)
• Yeh, C.-S., Wang, Z., Miao, F., Ma, H., Kao, C.-T., Hsu, T.-S., Yu, J.-H., Hung, E.-T., Lin, C.-C., Kuan, C.-Y., Zhou, C., Qu, G.-Z., Jiang, J., Liu, G., Wang, J. P., Li, W.*, Chiang, V. L.*, Chang, T.-H.*, Lin, Y.-C. J.*, 2019, “A novel synthetic-genetic-array based yeast one-hybrid system for high discovery rate and short processing time.”, Genome Research, 29(8),1343-1351. (SCIE)
• Chang, S.-L., Wang, H.-K., Tung, L., and Chang, T.-H.*, 2018, “Adaptive transcription-splicing resynchronization upon losing an essential splicing factor”, NATURE ECOLOGY & EVOLUTION, 2(11), 1818-1823. (SCIE)
• Chung, C.-y., Hsiao, Y.-m., Huang, T.-Y., Chang, T.-H.*, and Chang, C-c.*, 2018, “Germline expression of the hunchback orthologues in the asexual viviparous aphids: A conserved feature within the Aphididae”, Insect Molecular Biology, 27(6), 752-765. (SCIE)
• Chuang, T.-J., Chen, Y.-J., Chen, C.-Y., Mai, T.-L., Wang, Y.-D., Yeh, C.-S., Yang, M.-Y., Hsiao, Y.-T., Chang, T.-H., Kuo, T.-C., Cho, H.-H., Shen, C.-N., Kuo, H.-C., Lu, M.-Y., Chen, Y.-H., Hsieh, S.-C., and Chiang, T.-W., 2018, “Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells”, Nucleic Acids Research, 46(7), 3671-3691. (SCIE)
• Yeh, C.-S., Chang, S.-L., Chen, J.-H., Wang, H.-K., Chou, Y.-C., Wang, C.-H., Huang, S.-H., Larson, A., Pleiss, P. A., Chang, W.-h., and Chang, T.-H.*, 2017, “The conserved AU-dinucleotide at the 5’ end of nascent U1 snRNA is optimized for the interaction with nuclear cap-binding-complex”, NUCLEIC ACIDS RESEARCH, 45 (16), 9679-9693. (SCIE)
• Lee, F. F.-Y., Hui, C.-F., Chang, T.-H.*, Chiou, P. P.*, 2016, “Alternative Splicing of Toll-Like Receptor 9 Transcript in Teleost Fish Grouper Is Regulated by NF-κB Signaling via Phosphorylation of the C-Terminal Domain of the RPB1 Subunit of RNA Polymerase II”, PLOS ONE, 11(9), e0163415. (SCIE)
• Fu-Lung Yeh, Luh Tung, and Tien-Hsien Chang*, 2016, “Detection of protein-protein interaction within an RNA-protein complex via unnatural-amino-acid-mediated photochemical crosslinking”, Methods in Molecular Biology, 1421, 175-189.
• Chang, S. L., Leu, J.-Y.*, and Chang, T.-H.*, 2015, “A population study of killer viruses reveals different evolutionary histories of two closely related Saccharomyces sensu stricto yeasts”, Molecular Ecology, 24, 4312-4322. (SCIE)
• Hsiang-En Hsu, Tzu-Ning Liu, Chung-Shu Yeh, Tien-Hsien Chang, Yi-Chen Lo*, and Cheng-Fu Kao*, 2015, “Feedback control of Snf1 protein and its phosphorylation is necessary for adaptation to environmental stress”, Journal of Biological Chemistry, 290, 16786-16796. (SCIE)
• Chang, T.-H.*, Tung, L., Yeh, F.-L., Chen, J-H., and Chang, S.-L., 2013, “Functions of the DExD/H-box proteins in the nuclear pre-mRNA splicing pathway”, Biochimica et Biophysica Acta-Gene Regulatory Mechanisms, 1829, 764-774. (SCIE)
• Chang, C.-c., Hsiao, Y.-m., Huang, T.-Y., Cook, C. E., Shigenobu, S., and Chang, T.-H. , 2013, “Noncanonical expression of caudal during early embryogenesis in the pea aphid Acyrthosiphon pisum: maternal cad-driven posterior development is not conserved”, Insect Mol. Biol., 22(4), 442-455. (SCIE)
• Wang, C.-Y., Wen, W.-L., Nilsson, D., Sunnerhagen, P., Chang, T.-H., and Wang, S.-W., 2012, “Analysis of stress granule assembly in Schizosaccharomyces pombe”, RNA, 18, 694-703. (SCIE)
• Huang, J.-Y., Su, W.-C., Jeng, K.-S., Chang, T.-H.*, and Lai, M. M.-C.*, 2012, “Attenuation of 40S Ribosomal Subunit Abundance Differentially Affects Host and HCV Translation and Suppresses HCV Replication.”, PLoS Pathogens, 8(6), 1-14. (SCIE)
• Shea, F. F., Rowell, J. R., Li, Y., Chang, T.-H., and Alvarez, C. E., 2012, “Mammalian alpha arrestins link activated seven transmembrane receptors to Nedd4 family E3 ubiquitin ligases and interact with beta arrestins.”, PLoS One, 7(12), e50557. (SCIE)
• Shieh, G. S., Pan, C.-H,, Wu, J.-H., Sun, Y.-J., Wang, C.-C., Hsiao, W.-C., Lin, C.-Y., Tung, L., Chang, T.-H., Fleming, A. B., Hillyer, C., Lo, Y.-C., Berger, S.-L., Osley, M. A., and Kao, C.-F., 2011, “H2B ubiquitylation is part of chromatin architecture that marks exon-intron structure in budding yeast”, BMC Genomics, 12, 627. (SCIE)
• Su, C.-H., Shih, C.-H., Chang, T.-H., and Tsai, H.-K., 2010, “Genome-wide analysis of the cis-regulatory modules of divergent gene pairs in yeast.”, Genomics, 96, 352-361. (SCIE)
• 1. Chang, L.-C., Lin, Y.-C., Tung, L., Yeh, F.-L., Yeh, C.-S., and Chang, T.-H. ，2010，〈RNA helicases: promoting the conformation changes of cellular RNAs and RNPs〉，《Chemistry》，68(4), 259-270。(Others)
• Sung HM, Wang TY, Wang D, Huang YS, Wu JP, Tsai HK, Tzeng J, Huang CJ, Lee YC, Yang P, Hsu J, Chang T, Cho CY, Weng LC, Lee TC, Chang TH, Li WH, Shih MC, 2009, “Roles of trans and cis variation in yeast intraspecies evolution of gene expression.”, Molecular Biology and Evolution, 26(11), 2533-8. (SCIE)
• Hage, R., Tung, L., Du, H., Stands, L., Rosbash, M., and Chang, T.-H., 2009, “A targeted bypass screen identifies Ynl187p, Prp42p, Snu71p, and Cbp80p for stable U1 snRNP/pre-mRNA interaction”, Molecular and Cellular Biology, 29(14), 3941-3952. (SCIE)
• Woan-Yuh Tarn, Tien-Hsien Chang*, 2009, “The current understanding of Ded1p/DDX3 homologs from yeast to human”, RNA Biology, 6(1), 17-20. (SCIE)
• T. Burckin, R. Nagel, Y. Mandel-Gutfreund, L. Shiue, T. Clark, J.-L. Chong, T.-H. Chang, S. Squazzo, G. Hartzog and M. Jr. Ares, 2005, “Exploring functional relationships between components of the transcription, splicing, and mRNA export machineries by gene expression phenotype analysis”, Nat. Struct. Mol. Biol, 12, 175-182. (SCIE)
• J.-L. Chong, R.-Y. Chuang, L. Tung and T.-H. Chang, 2004, “Ded1p, a conserved DExD/H-box translation factor, can promote L-A virus negative-strand RNA synthesis in vitro”, Nucleic Acids Research, 32, 2031-2038. (SCIE)
• S. S.-I Tseng-Rogenski, J.-L. Chong, C. B. Thomas, S. Enomoto, J. Berman and T.-H. Chang, 2003, “Functional conservation of Dhh1p, a DExD/H-box protein in Saccharomyces cerevisiae”, Nucleic Acids Research, 31, 4995-5002. (SCIE)
• J. Y.-F. Chen, L. Stands, J. P. Staley, Jr. R. R. Jackups, L. J. Latus and T.-H. Chang*, 2001, “Specific alterations of U1-C protein or U1 small nuclear RNA can eliminate the requirement of Prp28p, an essential DEAD-box splicing factor”, Molecular Cell, 7, 227-232. (SCIE)
• S. S.-I Tseng, P. L. Weaver, Y. Liu, M. Hitomi, A. M. Tartakoff and T.-H. Chang, 1998, “A cyotosolic RNA helicase required for poly(A)+ RNA export”, EMBO J, 17, 2651-2662. (SCIE)
• Paul L. Weaver, C. Sun, Tien-Hsien Chang* , 1997, “Dbp3p, a putative RNA helicase in Saccharomyces cerevisiae, is required for efficient pre-ribosomal RNA processing predominantly site A3”, Mol. Cell. Biol., 17(3), 1354-1365. (SCIE)
• R.-Y. Chuang, P. L. Weaver, Z. Liu and T.-H. Chang, 1997, “Requirement of the DEAD-box protein Ded1p for messenger RNA translation”, Science, 275, 1468-1471. (SCIE)