Jiguo Chen Education Contact Information |
Statement of Research Interests
1). Virus-host cell interaction and global regulation of gene expression
A major challenge in the post-genome era is to elucidate global transcriptional regulatory networks in human cells during normal development and disease such as tumorigenesis. Transcription factors control gene expression through binding-specific regulatory sequences on their target genes. Alterations in gene expression in various normal biological processes such as growth and development, and in disease progression are, in part, a consequence of changes in the DNA-binding status of various transcription factors. Identifying these targets of transcription factors on a genome-wide scale is, therefore, fundamental for understanding transcriptional regulatory networks in human cells under various conditions. I recently developed a method called serial analysis of binding elements (SABE) for globally identifying binding sites of human transcription factors in vivo. Coupled with next generation sequencing technology, the SABE method circumvents the need for microarrays and is able to apply in human whole genome study in an unbiased manner.
2). Role of tumor virus in human tumorigenesis
A key unresolved question in tumor virology is why a benign viral infection for one individual turns to be a lethal cancer for another. Several lines of evidence indicate that it is not the virus itself but the interaction between the virus and host factors that determine the transition from chronic viral infection to the initiation of cancer. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a newly identified human tumor virus consistently detected in all forms of Kaposi’s sarcoma (KS), in primary effusion lymphoma (PEL) and in AIDS-associated multicentric Castleman’s disease (MCD). KSHV is believed to be an etiologic agent strictly necessary for the development of KS, yet very few infected people ever develop cancer. Primary to answering these questions is the development of an experimental cellular model to convert human normal cells into tumor cells using a defined set of KSHV genes. This cellular model will be used in the following studies: 1) To identify the minimal genetic requirements that reproduce the oncogenesis of KSHV in vitro; 2) To identify global alternations of gene transcriptional regulation induced by these KSHV genes; and 3) To identify biomarkers and molecular signatures that are specific for the switch from infection to the initiation of cancer.
3). Genetic switch on/off mechanisms
A hallmark of human herpesvirus infection is the establishment of latency. The switch from latent to lytic infection of Kaposi’s sarcoma-associated herpesvirus (KSHV) is initiated by a number of stimuli that induce the expression of the key lytic switch protein, RTA. The expression of Rta is necessary and sufficient to trigger the full lytic program resulting in the cascade expression of viral proteins, release of viral progeny, and host cell death. The expression of RTA is likely controlled by epigenetic modification of its promoter, especially by DNA methylation. My hypothesis is that the epigenetic modifications in the promoter region of RTA are key determinations governing viral latency and reactivation and may involve interplay between viral RTA and host factors that regulate chromosomal architecture. This project is to elucidate the genetic switch on/off mechanisms that govern KSHV latency and reactivation: 1) To establish a recombinant reporter virus replacing RTA gene in KSHV genome with luciferase reporter gene; 2) To study global gene regulation by RTA through protein-DNA and protein-protein interactions in response to various stimulations; 3) To identify key cellular factors/signal pathways leading to viral reactivation from latency.
Recent Publications
Chen, J. 2006. Serial analysis of binding elements for human transcription factors. Nature Protocols 1 (3): 1481-1493 link
Chen, J. & Sadowski, I. 2005. Identification of the mismatch repair genes PMS2 and MLH1 as p53 target genes by using serial analysis of binding elements. Proc. Natl. Acad. Sci. U.S.A. 102 (13): 4813-4818. link
Chen, J., Malcolm, T., Estable, M. C., Roeder, R. G. & Sadowski, I. 2005. TFII-I regulates induction of chromosomally integrated human immunodeficiency virus type 1 long terminal repeat in cooperation with USF. J. Virol. 79 (7): 4396-4406. link
Chen, J., Ueda, K., Sakakibara, S., Okuno, T., Parravicini, C., Corbellino, M. & Yamanishi, K. 2001. Activation of latent Kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator. Proc. Natl. Acad. Sci. U S A 98 (7): 4119-4124. . link