Human papillomaviruses (HPVs) induce a variety of human diseases including genital warts and cervical carcinomas. Regulation of HPV gene expression is mainly controlled by virus-encoded E2 proteins and cellular transcription factors. Although many studies have been conducted on HPV transcription using naked viral DNA genomes, very little is known about the molecular events leading to initiation of transcription from HPV chromatin, which represents a condensed form of the HPV genome in complex with cellular core histone proteins. Formation of chromatin prevents access of the cellular transcription machinery and thereby inhibits HPV gene expression. To identify protein factors that facilitate transcription from HPV chromatin and to further define the molecular mechanism underlying transcriptional events, we propose the following two aims. 1) To identify cellular proteins working in conjunction with HPV E2 protein. Naturally assembled E2- cellular complexes have been partially purified from human 293-derived cell lines that conditionally express different forms of FLAG-tagged HPV-11 E2 proteins. Our findings that human SWI/SNF chromatin remodeling complex, GCN5 histone acetyltransferase and general transcription factor TFIID are found in a 2-MDa E2-cellular complex and a different set of cellular proteins with putative corepressor function is associated with another E2-cellular complex suggest that the N-terminal domain of E2 may functionally recruit SWI/SNF, GCN5 and TFIID to initiate HPV chromatin transcription and also E2 may switch its interacting partners during the transcriptional process to further modulate HPV gene expression. These hypotheses will be tested by performing chromatin remodeling and histone acetyltransferase/deacetylase assays, as well as by conducting reconstituted cell-free transcription and protein-protein and protein-DNA interaction studies. 2) To dissect the functional role of E2-cellular complexes in HPV chromatin transcription. We will define the role of E2-cellular complexes by reconstituted HPV chromatin transcription assays using individually purified chromatin assembly factors as well as by in vivo chromatin immunoprecipitation studies using human HeLa-derived cell lines conditionally expressing different forms of HPV E2 and E1 proteins. Collectively, these studies will uncover the role of human SWI/SNF, GCN5, TFIID and other cellular factors in E2-mediated transcription of HPV chromatin, which mimics naturally occurring HPV genomes found in vivo, and also shed light on the molecular events leading to a productive initiation of chromatin transcription.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Virology Study Section (VR)
Program Officer
Blair, Donald G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Li, Xiangyi; Baek, GuemHee; Ramanand, Susmita G et al. (2018) BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Cell Rep 22:796-808
Bao, Lei; Chen, Yan; Lai, Hsien-Tsung et al. (2018) Methylation of hypoxia-inducible factor (HIF)-1? by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration. Nucleic Acids Res 46:6576-6591
Yu, Fang; Shi, Guang; Cheng, Shimeng et al. (2018) SUMO suppresses and MYC amplifies transcription globally by regulating CDK9 sumoylation. Cell Res 28:670-685
Wang, L-T; Chiou, S-S; Chai, C-Y et al. (2017) Transcription factor SPZ1 promotes TWIST-mediated epithelial-mesenchymal transition and oncogenesis in human liver cancer. Oncogene 36:4405-4414
Culleton, Sara P; Kanginakudru, Sriramana; DeSmet, Marsha et al. (2017) Phosphorylation of the Bovine Papillomavirus E2 Protein on Tyrosine Regulates Its Transcription and Replication Functions. J Virol 91:
Roberts, Thomas C; Etxaniz, Usue; Dall'Agnese, Alessandra et al. (2017) BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis. Sci Rep 7:6153
Wang, Ranran; Cao, Xing-Jun; Kulej, Katarzyna et al. (2017) Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinoma. Proc Natl Acad Sci U S A 114:E5352-E5361
Iftner, Thomas; Haedicke-Jarboui, Juliane; Wu, Shwu-Yuan et al. (2017) Involvement of Brd4 in different steps of the papillomavirus life cycle. Virus Res 231:76-82
Kim, Dong-Hyun; Kwon, Sanghoon; Byun, Sangwon et al. (2016) Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis. Nat Commun 7:12179
Shu, Shaokun; Lin, Charles Y; He, Housheng Hansen et al. (2016) Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529:413-417

Showing the most recent 10 out of 54 publications