Zhi-Ming Zheng, M.D., Ph.D.
RNA Biology Laboratory
Building 560, Room 11-86
Frederick, MD 21702
Viral RNA Splicing and Oncogenesis
Zheng first identified RNA cis-elements in regulation of alternative RNA splicing in papillomavirus in 1996 and has been studying protein-RNA interactions and their consequences in various infections with tumorviruses, including high-risk human papillomaviruses and Kaposi sarcoma-associated herpesvirus. This study aims to understand how RNA splicing and small regulatory RNAs regulate the expression of viral and host genes in viral carcinogenesis. The long-term goal is to develop a series of therapeutic approaches to control viral or cellular gene expression for cancer treatment and to identify biomarkers for clinical diagnosis and prognosis.
1) Papillomavirus infection and viral gene expression. Human papillomavirus type 16 (HPV16) or 18 (HPV18) infection, acquired primarily via sexual transmission, is widely recognized as a leading cause of cervical and anal cancer. Persistent infection with oncogenic or high-risk HPVs in other tissues also leads to the development of cancers. Two viral oncoproteins, E6 and E7, of oncogenic HPVs are involved in cervical carcinogenesis and are known to destabilize cellular tumor suppressor proteins and to induce aberrant expression of a subset of oncogenic and tumor-suppressive miRNAs. In HPV16- and HPV18-infected cells, E6 and E7 are transcribed as a single bicistronic E6E7 RNA bearing 3 exons and 2 introns, with the intron 1 in the E6 coding region. Splicing of the intron 1 in E6E7 pre-mRNA disrupts the E6 ORF, but is required to reinitiate translation of the E7 ORF downstream. Thus, RNA splicing regulates the production of viral E6 and E7.
We found that cellular RNA splicing factors, including SRSF3 (SRp20), control virus early-to-late switch through binding to viral RNA cis-elements. We demonstrated that SRp20 is a proto-oncogene essential for cell proliferation. When overexpressed, it induces tumor formation. Together, the HPV infection-induced degradation of host tumor suppressive proteins, aberrant expression of oncogenic and tumor-suppressive miRNAs, and enhancement of SRp20 expression could be three distinguishable mechanisms leading to the development of cervical cancer.
2) KSHV gene expression and post-transcriptional regulation. KSHV is a lymphotropic DNA tumor virus that induces Kaposi sarcoma (KS), primary effusion lymphoma (PEL) or body cavity-based B-cell lymphoma, and multicentric Castleman disease (MCD). Among those malignancies, KS occurs frequently in the patients infected with HIV. PEL and MCD feature increased levels of cytokines (IL6 and IL10). Latent KSHV infection in KS lesions and PEL-derived B cells can be reactivated as lytic KSHV infection by various stress conditions or inflammation.
In KSHV lytic infection, a viral lytic gene ORF57 (mRNA transcript accumulation or MTA) encodes a multifunctional, caspase-7 sensitive RNA-binding protein to regulate the expression of a subset of viral lytic genes at the posttranscriptional level. We demonstrated that ORF57 acts as a dimer to carry out this function by binding to the RNA MRE (MTA responsive element) and interacting with cellular RNA-binding proteins. ORF57 functions as a viral splicing factor to promote RNA splicing by interacting with the spliceosomal machinery and by attenuation of SRSF3 activities. ORF57 binds to and stabilizes viral RNAs by interaction with several host RNA-binding factors. ORF57 interacts with Ago2 adn GW182, two major components of RISC, to suppress formation of RNA-processing bodies and miRNA activitie. ORF57 also blocks PKR activation to inhibit stress granule formation and interferon induction and thus plays an important role in KSHV inhibition of host cell innate immunity.
Our lab has extensive collaborations on various projects with many investigators. Our current collaborators are Craig Meyers of Pennsylvania State University school of Medicine, Louise Chow of the University of Alabama at Birmingham school of Medicine, Paul Lambert of University of Wisconcin School of Medicine, Thomas Tuschl of Rockefeller University, Neil Christensen of Pennsylvania State University School of Medicine, Renske Steenbergen of VUMC Amsterdam, Xin Xie of Zhengjiang University School of Medicine Women's Hospital, Ke Lan of the State Key Laboratory of Virology, Wuhan University, Lifang Zhang of Wenzhou Medical University and Michael Kruhlak, Chuxia Deng, Jun Zhu, Donald Court, Shuo Gu, Yun-Xing Wang and Maggie Cam of NIH.
Dr. Zhi-Ming Zheng received his medical and virological training in China (1981) and was a Yale-China Exchange Scholar in clinical virology at Yale University (1981-1984). Dr. Zheng served as Associate Professor, Chief of the Clinical Virology Laboratory, and Deputy/Acting Director of the Virus Research Institute, Wuhan University School of Medicine, China (1985-1990). He was Vice-President of the Chinese Society of Medical Virology (1988-1990). He first isolated enterovirus type 71 (EV71, ATCC VR-1432) in China from the vesicle fluid of a hand, foot, and mouth disease patient and identified a new poxvirus named epidemic erythromelagia-related poxvirus (ERPV, ATCC VR-1431). He and John Huggins at the US Army Medical Research Institute of Infectious Diseases led the first double-blind, placebo-controlled clinical trial of intravenous ribavirin therapy for hemorrhagic fever with renal syndrome (HFRS) caused by hantavirus infection in China (1985-1989). This successful trial led to both the China FDA and the US Army to officially approve the ribavirin therapy for hantavirus infection in 1990. He received his Ph.D. from the University of South Florida School of Medicine (1994). He was an IRTA fellow and later a senior staff in the Laboratory of Tumor Virus Biology before heading his section in the HIV and AIDS Malignancy Branch in 2000, the Gene Regulation and Chromosome Biology Laboratory in 2013 and the RNA Biology Laboratory of NCI in 2016. His research interests center on the RNA processing and tumorigenesis of tumor viruses including papillomaviruses and Kaposi's sarcoma-associated herpesvirus. He organized the 24th International Papillomavirus Conference and Clinical Workshop, Beijing, China, Nov. 3-9, 2007 and was a recipient of the 2009 NCI Director Award, 2010 NIH Award of Merit, 2016 NCI Outstanding Mentor Award and 2016 NIH APAO Outstanding Scientific Achievement Award. He was elected as a member of the American Academy of Microbiology in 2014.
Ajiro M, Jia R, Yang Y, Zhu J, Zheng ZM. A genome landscape of SRSF3-regulated splicing events and gene expression in human osteosarcoma U2OS cells. Nucleic Acids Res. 2016;44(4):1854-70.
Majerciak V, Pripuzova N, Chan C, Temkin N, Specht SI, Zheng ZM. Stability of structured Kaposi's sarcoma-associated herpesvirus ORF57 protein is regulated by protein phosphorylation and homodimerization. J Virol. 2015;89(6):3256-74.
Wang X, Wang HK, Li Y, Hafner M, Banerjee NS, Tang S, Briskin D, Meyers C, Chow LT, Xie X, Tuschl T, Zheng ZM. microRNAs are biomarkers of oncogenic human papillomavirus infections. Proc Natl Acad Sci U S A. 2014;111(11):4262-7.
Massimelli MJ, Majerciak V, Kruhlak M, Zheng ZM. Interplay between polyadenylate-binding protein 1 and Kaposi's sarcoma-associated herpesvirus ORF57 in accumulation of polyadenylated nuclear RNA, a viral long noncoding RNA. J Virol. 2013;87(1):243-56.
Wang X, Meyers C, Wang HK, Chow LT, Zheng ZM. Construction of a full transcription map of human papillomavirus type 18 during productive viral infection. J Virol. 2011;85(16):8080-92.
Related Scientific Focus Areas
Microbiology and Infectious Diseases
Molecular Biology and Biochemistry
This page was last updated on September 12th, 2019