Chungming Chang, Ph.D.
Institute of Molecular and Genomic Medicine
Ph.D., Department of Microbiology and Immunology, Temple University, USA (1974)
B.S. Department of Biology, Tunghai University, Taiwan (1969)
2001-2003 Director, National Science and Technology Priority, Program in Pharmaceutical and Biotechnology (國科會生技製藥國家型計畫總主持人)
2001-2002 Acting Director, Division of Biotechnology and Pharmaceutical Research
1997-2006 Director, Department of Intramural Research Affairs
2009-2011 Interim Director, Division of Infectious Diseases, National Health Research Institutes
Feb.2012-Dec.2012 Acting Director, Office of Student affairs, National Health Research Institutes
2011-2013 Chairman of Advices Committee, Institute of Infectious Disease and Vaccine Research
May 2013-Mar. 2014 Interim Director, Institute of Biotechnology and Pharmaceutical Research
1997-2016 Distinguished Investigator, Institute of Molecular and Genomic Medicine, National Health Research Institutes
2012-2016 Chairman, NHRI Biobank Ethic Committee
2013-2016 Chairman, Task Force for NHRI Spin-off
2013-2015 Chairman, Advisory Board Committee, National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes
2014-2016 Chairman, Task Force for NHRI Cost-Benefit Analysis
1974-1977 Forgarty Visiting Fellow, Laboratory of Cell Biology, NCI, NIH
1977-1978 Adjunct Assistant Professor, Dept. of Microbiology, School of Medicine, Temple University
1977-1978 Visiting Associate, National Cancer Institute, NIH
1984-1985 Visiting Scientist, Dept. of Tumor Biology, Karolinska Institute, Sweden
1978-1981 Associate Professor, Institute of Microbiology and Immunology, National Yang-Ming University
1981-1988 Director, Graduate Institute of Microbiology and Immunology, National Yang-Ming Medical College
1991-1994 President, The Chinese Society of Immunology
1994-1995 Interim Dean, School of Life Sciences, National Yang-Ming University
1978-1997 Investigator, Laboratory of Tumor Biology, Dept. of Medical Research, Veterans General Hospital, Taipei
1991-1996 Dean of Academic Affairs, National Yang-Ming University
1999-2003 President, Chinese Society of Cell and Molecular Biology
2003-2007 Secretary General, Asia-Pacific Organization for Cell Biology
2007-2014 Vice President, Asia-Pacific Organization for Cell Biology
1981-present Adjunct Professor, Institute of Microbiology and Immunology, National Yang-Ming University
2001-present Chairman, Board of Trustees, Fung Chia University
Dr. Chang’s recently research is focus on regulation of HBV replication and hepatocyte differentiation by inflammatory cytokines and biological functions of HBV spliced RNAs. The pathogenesis of HBV-induced liver diseases involves complicated mechanisms revolving around viral replication and immune responses against HBV infection. Dr. Chang’s team has established a HBV-producing cell line capable of replicating virus efficiently. This provides a suitable model for investigating the regulation of HBV replication. They found that HBV replication can be effectively suppressed by TGF-β1 or IL-6, primarily through inhibition of viral transcription or assembly of viral capsids. The decreased level of HNF-4α was mediated through the antiviral effect of TGF-β1 and the activation of PI-3K signaling pathway was involved in the antiviral effect of IL-6. We also found that growth arrest can simultaneously induce cell differentiation and enhance HBV replication. These results indicate that HBV replication can be regulated by inflammation induced in CHB, which is mediated by cytokines and growth/differentiation status of hepatocytes. Further characterization of the molecular mechanisms and signal pathways involved in the regulation of HBV replication by TGF-β1 and IL-6, and differentiation status of hepatocytes is helpful to understand the overall regulation mechanism by which infected hepatocytes regulate the virus amplification and clearance. In addition, they will provide the framework for the design of drugs to control HBV replication during the progression of chronic hepatitis B virus infection (CHB).
Hepatitis B virus (HBV) has been classified into eight genotypes (A to H) based on divergence in genomic sequences. Several studies revealed a close association between HBV genotypes and disease progression. However, the mechanism involved in the clinical relevance of these genotypes is not well understood. Transcription of HBV genes primarily consists of four unspliced transcripts that encode viral proteins for HBV replication. In addition to unspliced RNAs, several spliced RNAs have been identified in HBV genome-transfected cells and infected liver tissues. The expression of spliced RNAs was demonstrated as relating to the viral life cycle and clinical outcomes of liver diseases. Dr. Chang’s team characterized and estimated the population of spliced RNAs in either HBV genotype D- or genotype A-transfected HepG2 cells by sequencing of random-packing colonies. They revealed that the species and frequency of spliced RNAs were dramatically different between these two genotypes. Multiple splicing events occurred more frequently in genotype A-transfected cells compared with that in genotype D. furthermore, the significance of these distinct populations of HBV spliced RNAs in viral replication and host-virus interactions during disease progression is worthy of further investigation.
For the past years, Dr. Chang’s team has been devoted to understanding the roles of the spliced viral RNAs on regulating HBV replication. Using cultured human hepatoma cells as a model of HBV infection, they found that the expression of 2.2DS-RNA caused a decrease in HBV replication. In cultured cells, the ectopic expression of 2.2DS-RNA obviously reduced the intracellular levels of HBV mRNAs. Their analysis of the 2.2DS-RNA-mediated suppression of viral RNA expression showed that 2.2DS-RNA inhibited transcription via binding to the TATA-binding protein and stress granule proteins. There findings suggest that the 2.2DS-RNA acts as a suppressive noncoding RNA that modulates HBV replication, which may in turn influence the development of chronic hepatitis B. These results will provide a framework for better understanding of the regulation of HBV replication and the biological functions of these spliced RNAs. Furthermore, this knowledge will provide insights into developing a novel therapeutic strategy for curing CHB patients.
HIGHLIGHTS OF RECENT RESEARCH
Patients infected with certain genotypes of HBV have a lower risk of hepatocellular carcinoma and exhibit a more favorable response to antiviral therapy than patients infected with other HBV genotypes. Using cultured human hepatoma cells as a model of HBV infection, we found that the expression of 2.2DS-RNA caused a decrease in HBV replication. In cultured cells, the ectopic expression of 2.2DS-RNA obviously reduced the intracellular levels of HBV mRNAs. Our analysis of the 2.2DS-RNA-mediated suppression of viral RNA expression showed that 2.2DS-RNA inhibited transcription via binding to the TATA-binding protein and stress granule proteins. Our findings suggest that the 2.2DS-RNA acts as a suppressive noncoding RNA that modulates HBV replication, which may in turn influence the development of chronic hepatitis B. (J Virol. (2015))
Hepatitis B virus reactivation is an important medical issue in cancer patients who undergo systemic chemotherapy. Up to half of CHB carriers receiving chemotherapy develop hepatitis and among these cases a notable proportion are associated with HBV reactivation. However, the molecular mechanism(s) through which various chemotherapeutic agents induce HBV reactivation is not yet fully understood. In this study, we investigated the role of the cell cycle regulator p21 (Waf1/Cip1) in the modulation of HBV replication when a common chemotherapeutic agent, doxorubicin, is present. We showed that p21 expression was increased by doxorubicin treatment. This elevation in p21 expression enhanced the expression of CCAAT/enhancer-binding protein α (C/EBPα); such an increase is likely to promote the binding of C/EBPα to the HBV promoter, which will contribute to the activation of HBV replication. Our current study thus reveals the mechanism underlying doxorubicin modulation of HBV replication and provides an increased understanding of HBV reactivation in CHB patients who are receiving systemic chemotherapy. (PLoS ONE (2015))
Hepatitis B virus (HBV) is the smallest DNA virus and the major cause of acute and chronic hepatitis. The 3.2 kb HBV viral genome generates four major species of unspliced viral transcript as well as several alternatively spliced RNAs. A 2.2 kb singly-spliced RNA is the most abundant spliced RNA and is widely expressed among all HBV genotypes. The expression of the singly-spliced RNA, as well as that of its encoded protein HBSP, is strongly associated with hepatopathology during HBV infection. Here, we report a novel inhibitory role of a p21.5 protein, which is encoded by a 2.2 kb singly-spliced RNA, in the modulation of HBV replication. We show that overexpression of the singly-spliced RNA is able to efficiently inhibit HBV replication. Furthermore, a mutation in the ATG start codon of the precore region completely abolishes the inhibitory effect of the singly-spliced RNA, indicating that a viral protein (p21.5) derived from the singly-spliced RNA is the mediator of the inhibition. Furthermore, p21.5 is able to form a homodimer that interacts with core dimers forming hybrid viral assembly components. Sucrose gradient fractionation revealed that co-expression of p21.5 resulted in a spread distribution pattern of core proteins ranging from low to high sucrose densities. When compared with p22, p21.5 is almost ten times more efficient at destabilizing HBV nucleocapsid assembly in Huh7 cells overexpressing either p21.5 or p22 protein. Moreover, in vivo expression of p21.5 protein by tail vein injection was found to decrease the amount of nucleocapsid in the livers of HBV-expressing BALB/c mice. In conclusion, our study reveals that the HBV 2.2 kb singly-spliced RNA encodes a 21.5 kDa viral protein that significantly interferes with the assembly of nucleocapsids during HBV nucleocapsid formation. These findings provide a possible strategy for elimination of HBV particles inside cells. (PLoS ONE (2015))
HONORS & AWARDS
1986 Tjing Ling Basic Medical Research Foundation
1994 Academic award, Ministry of Education 教育部學術獎(醫科)
1986-1996 Outstanding research award, National Science Council, R.O.C. 國科會傑出研究
Dr. Chang has been very active in academic activities in Taiwan and Asia Pacific region. He was elected as the President of Chinese Immunologist Society (Taipei) and Chinese Cell Biology Society (Taipei). He is now serving as the Secretary General of APOCB (Asian-Pacific Cell Biology Society). Dr. Chang has authored more than 100 papers and hosted several international conference and symposia.
- Tsai KN, Chong YC, Chou YC, Huang CC, Wang YL, Chen ML, Hsu JC, Wang SW, Chen CH* and Chang C*. Hepatitis B virus doubly spliced RNA represses viral and cellular genes by sequestering TATA-binding protein in assembly of stress granules. J Virol 2015, 89:11406-19.
- Wang YL, Liou GG, Lin CH, Chen ML, Kuo TM, Tsai KN, Huang CC, Chen YL, Huang LR, Chou YC, Chang C*. The inhibitory effect of the hepatitis B virus singly-spliced RNA-encoded p21.5 protein on HBV nucleocapsid formation. PLoS One 2015, 10:e0119625.
- Yang CC, Hu HS, Wu RH, Wu SH, Lee SJ, Jiaang WT, Chern JH, Huang ZS, Wu HN, Chang CM, Yueh A. A novel, potential dengue virus NS2B/NS3 protease inhibitor, BP13944, was discovered through high-throughput screening with dengue replicon cells. Antimicro Agents Chemother 2014, 58:110-9.
- Li WT, Hwang DR, Song JS, Chen CP, Chuu JJ, Hu CB, Lin HL, Huang CL, Huang CY, Tseng HY, Lin CC, Chen TW, Lin CH, Wang HS, Shen CC, Chang C, Chao YS and Chen CT. Synthesis and biological activities of 2-amino-1-arylidenamino imidazoles as orally active anticancer agents. J Med Chem 2010, 53:2409-17.
- Chong CL, Huang SF, Hu CP, Chen YL, Chou HY, Chau GY, Shew JY, Tsai YL, Chen CT, Chang C*, Chen ML. Decreased expression of UK114 is related to the differentiation status of human hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 2008, 17:535-42. (Cover Story)
- Chou YC, Chen ML, Chen YL, Chong CL, Ysai YL, Liu TL, Jeng KS, Hu CP, Chang C*. Suppression of Hepatitis B virus replication by TGF-beta1 is primarily mediated through the transcriptional inhibition of pregenomic RNA. Hepatology 2007, 46:672-81.
- Chou YC, Jeng KS, Chen ML, Liu HH, Liu TL, Chen YL, Liu YC, Hu CP, Chang C*. Evaluation of hepatitis B virus transcriptional efficiency for covalently closed circular DNA by RT-PCR combined with restriction enzyme digestion method. J Virol 2005, 79:1813-23.
- Sung CH, Hu CP, Hsu HC, Ng AK, Chou CK, Ting LP, Su TS, Han SH, Chang C*. Expression of class I and class II major histocompatibility antigens on human hepatocellular carcinoma. J Clin Invest 1989, 83:421-9.
- Chang C, Jeng KS, Hu CP, Lo SJ, Su YS, TiNg LP, Chou CK, Han SH, Pfaff E, Salfeld J, and Schaller H. Production of hepatitis B virus in vitro by transient expression of cloned HBV DNA in a hepatoma cell line. EMBO 1987, 6:675-80.
- Chang C, Luborsky SW and Mora PT. Tumor-specific transplantation antigen from SV40 transformed cells binds to DNA. Nature 1977, 269:438-40.