Zhi-Ming Zheng, M.D., Ph.D.
Dr. 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 tumor viruses, including high-risk human papillomaviruses and Kaposi’s 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 or AIDS treatments and to identify biomarkers for clinical diagnosis and prognosis.
1) RNA processing, 2) RNA-protein interactions, 3) regulatory RNAs, 4) tumor viruses
Gene Expression and Post-Transcriptional Regulation of DNA Tumor Viruses
1) Papillomavirus infection and viral and host 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 as well as oropharyngeal cancer. Persistent infection with these oncogenic or high-risk HPVs leads to HPV genome integration randomly into the host genome, which plays a critical role in the progression of cervical dysplasia and ultimately the development of cervical cancers. Mouse papillomavirus type 1 and cotton-tail rabbit papillomavirus infection models are two gold-standard preclinical animal models for studying HPV-associated infections and tumors. Two viral oncogenes, E6 and E7, are responsible for papillomaviral carcinogenesis and are highly expressed from the integrated viral genome. Oncogenic HPV E6 and E7 destabilize cellular tumor suppressor proteins and induce aberrant expression of a subset of oncogenic and tumor-suppressive microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). In HPV16 and HPV18, 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 open reading frame (ORF) but is required to reinitiate translation of the E7 ORF downstream. Thus, RNA splicing regulates the production of viral E6 and E7 and this splicing is controlled by a branch point adenosine at nt 385 in the E6 intron of HPV16 and by two alternative branch point adenosines either at nt 384 or at nt 388 in the E6 intron of HPV18. We found that cellular RNA-splicing factors, including SRSF3 (SRp20), also control RNA splicing of the viral early transcripts and viral early-to-late switch through binding to viral RNA cis-elements. We demonstrated that SRp20 is a proto-oncogene essential for cell proliferation by regulating genome-wide RNA splicing of several hundred host genes. When overexpressed, SRp20 induces cell transformation and tumor formation. Together, the HPV infection-induced degradation of host tumor suppressive proteins, aberrant expression of oncogenic and tumor-suppressive miRNAs and lncRNAs, and enhancement of SRp20 expression could be the major distinguishable mechanisms leading to the development of cervical cancer.
2) Kaposi's sarcoma-associated herpesvirus (KSHV) gene expression and post-transcriptional regulation. KSHV is a lymphotropic DNA tumor virus that induces Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) or body cavity-based B-cell lymphoma, and multicentric Castleman disease (MCD). Among these malignancies, KS occurs frequently in patients who are 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, the viral lytic gene ORF57 encodes a multifunctional, caspase-7-sensitive protein to regulate the expression of a subset of viral lytic genes at the post-transcriptional level. We solved the ORF57 crystal structure both as a dimer at 3.5 angstroms and as a monomer at 3 angstroms. We demonstrated that ORF57 functions as a dimer in the cells and carries out its functions by binding to RNA and interacting with cellular RNA-binding proteins. As a viral splicing factor first identified by us in the virology field, ORF57 promotes RNA splicing by interacting with the spliceosomal machinery and by attenuating SRSF3 activities. ORF57 binds to and stabilizes viral RNAs by interacting with host RNA capping, export, and polyadenylation factors. ORF57 also promotes protein translation by interrupting miRNA-mediated RNA instability and translational repression. Our recent findings indicate that ORF57 inhibits host innate immunity against lytic KSHV infection by interacting with PACT, PKR, Ago2, and GW182, leading to blocked formation of stress granules and P-bodies.
Our lab has extensive collaborations on various projects with many investigators. Our current collaborators are Craig Meyers, Pennsylvania State University School of Medicine; Louise Chow, University of Alabama at Birmingham School of Medicine; Paul Lambert, University of Wisconsin School of Medicine; Thomas Tuschl, Rockefeller University; Neil Christensen, Pennsylvania State University School of Medicine; Renske Steenbergen, VUMC Amsterdam; Xin Xie, Zhengjiang University School of Medicine Women's Hospital; Ke Lan, State Key Laboratory of Virology, Wuhan University; Lifang Zhang, Wenzhou Medical University; and Michael Kruhlak, Chuxia Deng, Jun Zhu, Yun-Xing Wang, and Maggie Cam, NIH.
Selected Recent Publications
- Proc Natl Acad Sci U S A. 118: e2014195118, 2021. [ Journal Article ]
- Lancet. 395: 949-950, 2020. [ Journal Article ]
Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment.PLoS Pathog. 16: e1008206, 2020. [ Journal Article ]
Novel EBV LMP-2-affibody and affitoxin in molecular imaging and targeted therapy of nasopharyngeal carcinoma.PLoS Pathog. 16: e1008223, 2020. [ Journal Article ]
CRISPR/Cas9-mediated knockout and in situ inversion of the ORF57 gene from all copies of the Kaposi's sarcoma-associated herpesvirus genome in BCBL-1 cells.J. Virol. 93: pii: e00628-19, 2019. [ Journal Article ]
Dr. 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). He 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). Dr. Zheng 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 U.S. 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 U.S. Army to officially approve the ribavirin therapy for hantavirus infection in 1990. Dr. Zheng received his Ph.D. from the University of South Florida School of Medicine (1994). He was an IRTA fellow and later a senior staff member in the National Cancer Institute 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, the RNA Biology Laboratory in 2016, and the HIV Dynamics and Replication Program in 2020. His research interests center on the RNA processing, RNA-protein interactions, 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, in 2007 and was a recipient of the 2009 NCI Director's Award, 2010 NIH Award of Merit, 2016 NCI Outstanding Mentor Award, and 2016 NIH Asian and Pacific Islander American Organization (APAO) Outstanding Scientific Achievement Award. He was elected as a member of the American Academy of Microbiology in 2014.
|Beatriz Alvarado Hernandez Ph.D.||Postdoctoral Fellow (CRTA)|
|Ayslan Brant Ph.D.||Postdoctoral Fellow (Visiting)|
|Deanna Gotte||Research Biologist|
|Haibin Liu Ph.D.||Postdoctoral Fellow (Visiting)|
|Vladimir Majerciak, Ph.D.||Associate Scientist|
|Lulu Yu Ph.D.||Postdoctoral Fellow (Visiting)|
Professor and Chair
Department of Microbiology, Wenzhou Medical University, China
Department of Pathology, Georgetown University
Case Western Reserve University
University of California, Riverside
Department of Pathology, Hyogo College of Medicine, Japan
U.S. Food and Drug Administration
Professor and Deputy Director
Wuhan University School of Stomatology, China
International Regulatory Group, R-Pharm, Moscow
JK BioPharma Solution, Inc., Maryland
Maastricht University, The Netherlands
Zhejiang University Women's Hospital, China
National Cancer Institute, NIH
General Dynamics Information Technology USA
Zhejiang University University Women's Hospital, China
Virology Laboratory, China Medical University, Shengyang, China
Kyoto University, Japan
Professor and Associate Dean
Wenzhou Medical University, China
Jamia Hamdard University, Delhi, India
Tianjin Medical University Dental School, China
Wenzhou Medical University, China
Graduate Student Candidate
University of Colorado
Congratulations to our 2020 ASV Travel Award recipents: Dr. Haibin Liu, Dr. Lulu Yu and Dr. Beatriz Alvarado Hernandez
Congratulations to our 2020 Travel Award recipient
Beatriz Alvarado Hernandez CRTA - Best Oral Presentation at the HIV & Cancer Virology Think Tank Meeting
Congratulations to our FARE2019 Winner – Fellows Award for Research Excellence
Congratulations to our FARE2018 Winner – Fellows Award for Research Excellence
Congratulations to our 2018 Travel Award recipient
Andrew Beltcappellino CRTA - Best Poster Presentation at the HIV & Cancer Virology Think Tank Meeting & 2017 NIH Postbac Poster Day Award
- Changes in in miRNAs Signal High-Risk HPV Infections (CCR News - 2014)
- Dr. Zheng Elected to the American Academy of Microbiology (NCI at Frederick Poster - 2014)
News about Dr. Zheng’s discovery on HPV oncogenes and host miRNAs
- Molecule Provides Clues about How Infection with Human Papillomavirus May Lead to Cancer (NIH news release - 2009)
The Zheng Lab
Top row (left to right): Zhi-Ming Zheng and his wife, Vladimir Majerciak, Haibin Liu and his wife and son
Bottom row (left to right): Deanna Gotte and her husband, Lulu Yu and her husband, Beatriz Alvarado Hernandez and her husband
Not shown: Ayslan Brant and his wife
Current Lab Members
Beatriz Alvarado Hernandez, Ph.D., Postdoctoral Fellow (CRTA)
Beatriz earned her Ph.D. in infectomics and molecular pathogenesis from the Center for Research and Advanced Studies, Mexico under the mentorship of Dr. Lorena Gutierrez. She is investigating how host RNA processing is regulated by direct binding of the Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic protein ORF57. Beatriz was awarded for the best oral presentation at the 2019 CCR HIV/AIDS & Cancer Virology Think Tank. She also recently received a travel award at the American Society for Virology (ASV) annual meeting (ASV2020).
Ayslan Brant, Ph.D., Postdoctoral Fellow (Visiting)
Ayslan earned his Ph.D. in genetics from Rio de Janeiro Federal University (UFRJ), Brazil, under the mentorship of Dr. Miguel Moreira, Brazilian National Cancer Institute (INCA) and co-mentorship of Dr. Zhi-Ming Zheng (HIV DRP). His work is focused on understanding how SARS-CoV-2 synthesizes its subgenomic RNAs (sgRNAs) for virus replication. Recently Ayslan received a travel award from and was invited to serve as a session co-chair at the International Papillomavirus Conference (IPVC2020) in Barcelona.
Deanna Gotte, M.S., Research Biologist
Deanna earned her M.S. in applied microbiology from Northern Arizona University. She provides laboratory support for the Zheng lab. Her current research is focused on understanding the role of nonsense-mediated RNA decay in human papillomavirus (HPV) RNA processing and half-life. Deanna’s research career has spanned over many disciplines including retroviral proteases, HIV-1 subtype analysis, and transcription fidelity of Saccharomyces cerevisiae RNA polymerase II.
Haibin Liu, Ph.D., Postdoctoral Fellow (Visiting)
Haibin earned his Ph.D. in microbiology from the College of Life Science, Wuhan University, China, under the mentorship of Dr. Gengfu Xiao. He currently studies human papillomavirus (HPV) regulation of long noncoding RNA (lncRNA) expression and function in cervical carcinogenesis. He is a winner of the NIH Fellows Award for Research Excellence (FARE) in 2018 and the ASV Travel Award in 2020.
Vladimir Majerciak, Ph.D., Associate Scientist
Vladimir earned his Ph.D. in virology from Comenius University and the Institute of Virology, Slovak Academy of Sciences in Bratislava, Slovakia. His current research is mainly focused on Kaposi’s sarcoma-associated herpesvirus (KSHV) and KSHV RNA-binding protein ORF57. Recently, he has expanded his study to include other tumor viruses, with a focus on virus-host interactions, viral protein structure, and viral transcriptome profiling. He was promoted to Staff Scientist in 2011 and to Associate Scientist in 2019. Read more about Vladimir in his CCR investigator profile.
Lulu Yu, Ph.D., Postdoctoral Fellow (Visiting)
Lulu earned her Ph.D. in cancer epidemiology from Peking Union Medical College, China, where she conducted human papillomavirus (HPV) epidemiology studies on cervical cancer in the general population under the mentorship of Dr. Youlin Qiao. Currently she is studying how papillomaviruses and the cellular splicing factor SRSF3 (SRp20) regulate RNA-binding protein expression, RNA splicing and other RNA processing, and oncogenesis. She is a winner of the NIH Fellows Award for Research Excellence (FARE) in 2019 and the ASV Travel Award in 2020.
Previous Zheng Lab Photos
Left to right: Haibin Liu, Deanna Gotte, Beatriz Hernandez, Thomas Zheng, Mina Griffioen, Lulu Yu, Vladimir Majerciak
Front row (left to right): Mina Griffioen, Beatriz Hernandez, Vladimir Majerciak
Back row (left to right): Thomas Zheng, Deanna Gotte, Lulu Yu, Haibin Liu
Front row (left to right): Tingtine Zhang, Lulu Yu, Beatriz Hernandez, Vladimir Majerciak, Ayslan Brant
Back row (left to right): Deanna Gotte, Thomas Zheng, Andrew BeltCappellino, Pengfei Jiang, Haibin Liu
Front row: Vladimir Majerciak
Back row (left to right): Thomas Zheng, Nishi Sharma, Haibin Liu, Masahiko Ajiro, Xiang Yang Xue
Left to right: Masahiko Ajiro, Yanping Ma, Junfen Xu, Echo Zhang, Thomas Zheng, Vincent Homman, Vladimir Majerciak, Nishi Sharma
Front row (left to right): Vincent Homman, Yanping Ma, Xiaohong Wang, Junfen Xu
Back row (left to right): Nishi Sharma, Vladimir Majerciak, Thomas Zheng, Masahiko Ajiro
Front row (left to right): Vladimir Majerciak, Nishi Sharma, Xiaohong Wang
Back row (left to right): Masahiko Ajiro, Xiaofan Li, Thomas Zheng