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Jianxin You, Ph.D.

Jianxin You, Ph.D.

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Associate Professor of Microbiology
Department: Microbiology
Graduate Group Affiliations

Contact information
Department of Microbiology
University of Pennsylvania Perelman School of Medicine
201C Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104-6076
Office: 215-573-6781
Fax: 215-898-9557
M.S. (Biochemistry and Molecular Biology)
University of Maine, 1996.
Ph.D. (Biochemistry and Molecular Biology)
Johns Hopkins, 2001.
Postdoc (Pathology)
Harvard Medical School, 2006.
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Description of Research Expertise

Research Interests
Human papillomaviruses, Merkel cell polyomavirus, virus-host interaction during viral persistent latent infection and tumorigenesis

Key words: DNA tumor viruses, Host targets, Persistent viral latent infection, Viral oncogenesis, Tumor virology, Bromodomain protein BRD4 and cancer

Research Summary
About 15% of cancers worldwide are caused by viral infection. Research in my lab investigates two oncogenic DNA tumor viruses: human papillomavirus (HPV) and Merkel cell polyomavirus (MCV). We are also studying the functional regulation of BRD4, which is not only an important host target for HPV and MCV but also a critical therapeutic target for a large number of cancers. Our overall research goal is to understand how the molecular interplay between the tumorigenic DNA viruses and their host targets leads to cancers.

MCV Infection and Merkel Cell Carcinoma: MCV is a novel human polyomavirus recently discovered in Merkel cell carcinoma (MCC), a highly aggressive form of skin cancer. Clonal integration of MCV into the host genome has been observed in ~80% of MCC. MCV is also an abundant virus frequently shed from healthy human skin. However, the mechanisms for MCV-induced oncogenesis and many aspects of the MCV life cycle remain poorly understood. Our recent studies offered novel insights to elucidate the life cycle and oncogenic mechanism of this newly discovered DNA tumor virus. To uncover MCV oncogenic mechanism, we will determine the origin cells for MCC tumors and investigate how MCV infection drives the oncogenic progression. Excessive exposure to ultraviolet (UV) radiation, immunosuppression, and advancing age are the most important risk factors for MCV-associated MCC skin cancers. Building on our previous finding that host DNA damage response factors contribute to MCV replication, we will investigate the role of UV and ionizing radiation in promoting MCV-induced skin cancer. MCV-associated MCC predominately occurs in elderly and immunocompromised patients. Using MCV as a model system, we will also examine how DNA viruses modulate host immune response to achieve latent infection and how abrogation of this process leads to viral induced oncogenesis.

Development of new antiviral strategies to abrogate HPV-host interaction during latent infection: High-risk HPV infection is the primary risk factor for cervical, anogenital, and head and neck cancers. Currently available HPV vaccines protect against up to four major types of cancer-causing HPV strains. However, the vaccines do not protect against the other over 140 HPV types and are not useful for those people who are already infected. Alternative approaches are therefore needed for curing ongoing HPV infections. This is particularly important because high-risk HPVs need to persistently infect host cells for years or even decades in order to accumulate substantial cytogenetic changes for developing invasive tumors. HPVs establish persistent infection by maintaining their genomes as episomes in infected cells. Our previous work identified BRD4 as the long sought-after receptor, which tethers the viral E2 protein/episome complex to mitotic chromosomes in latently infected cells thereby ensuring the faithful partitioning of viral episomes to daughter cells during mitosis. The HPV E2 interaction with BRD4 has been proven by us and many others to be important for HPVs to establish persistent infection in the host cells as well as for many aspects of the HPV life cycle. This HPV and host interaction has therefore become an attractive antiviral target. Using functional assays such as MAPPIT and BiFC to recapitulate the E2-Brd4 interaction in live cells, we will screen for drugs to inhibit the HPV-host interaction mediated by E2 and BRD4. The goal of this project is to develop affordable and effective new antiviral drugs to cure persisting HPV infections that are not protected by the HPV vaccines.

Regulation of BRD4 function and cancer: BRD4 is an epigenetic reader that plays a central role in transcriptional regulation, cellular growth control, and cell cycle progression. Dysregulation of BRD4 function has been implicated in the pathogenesis of a large number of cancers including acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, diffuse large B cell lymphoma, breast cancer, colon cancer, and ovarian carcinoma. BRD4 is also the target of translocation t(15;19), which results in the formation of BRD4-NUT fusion oncogene that accounts for the highly lethal transforming activity of NUT midline carcinoma (NMC). Although BRD4 has emerged as a key cancer therapeutic target, the mechanisms that regulate BRD4 function have not been elucidated. How alteration of BRD4 function leads to cancer also remains largely unknown. We reported that BRD4 preferentially occupies pluripotency genes in embryonic and cancer stem cells to regulate their transcription. Others also showed that BRD4 disproportionately enriches at a subset of key oncogenic genes and selectively stimulates their expression to drive cancer cell proliferation. Together, these findings support that BRD4 is not a universal epigenetic reader but rather a gene-specific transcription regulator. Our future studies will investigate the important questions regarding the mechanistic regulation of BRD4 function during cancer development. We will elucidate the upstream cellular signaling pathways that regulate BRD4 transcription function. We will also investigate the molecular mechanisms that control its gene-specific chromatin targeting. Using oncogenic DNA tumor viruses and cancer-associated genetic mutations as molecular probes, we will investigate how dysfunction of this important epigenetic reader lead to human cancers. Together, these studies will open the opportunities for developing effective treatment approaches for BRD4-associted cancers.

Rotation Projects:
Depending on the interests of the student, there are several possible projects in the areas described above. Prospective students are encouraged to contact Dr. You to discuss possible rotation projects.

Lab personnel:
Sabrina Tsang, Ph.D. Student
Ranran Wang, Postdoctoral fellow
Wei Liu, Postdoctoral fellow
Enxhi Rrapi, Research assistant
Hari Magge, Research assistant

Selected Publications

Wang R, You J.: Mechanistic Analysis of the Role of Bromodomain-Containing Protein 4 (BRD4) in the BRD4-NUT Oncoprotein Induced Transcriptional Activation. J Biol Chem. 290(5): 2744-58, Jan 2015.

Li J, Diaz J, Wang X, Tsang SH, You J. : Phosphorylation of Merkel Cell Polyomavirus Large T Antigen at Serine 816 by ATM Kinase Induces Apoptosis in Host Cells. J Biol Chem. 290(3): 1874-84, Jan 2015.

Liu W, Stein P, Cheng X, Yang W, Shao NY, Morrisey EE, Schultz RM, You J.: BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos. Cell Death Differ. 21(12): 1950-60, dec 2014.

Wang R, Liu W, Helfer CM, Bradner JE, Hornick JL, Janicki SM, French CA, You J: Activation of SOX2 expression by BRD4-NUT oncogenic fusion drives the cellular transformation in NUT midline carcinoma. Cancer Research 74(12): 3332-43, Jun 2014.

Tsang SH, Wang X, Li J, Buck CB, You J: Host DNA Damage Response Factors Localize to Merkel Cell Polyomavirus DNA Replication Sites to Support Efficient Viral DNA Replication. J Virol 88(6): 3285-97, Jan 2014.

Li J, Wang X, Diaz J, Tsang SH, Buck CB, You J: Merkel Cell Polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation. J Virol 87(16): 9173-88, Aug 2013 Notes: Chosen as a JVI Spotlight Feature article.doi: 10.1128/JVI.01216-13.

Wang X, Helfer CM, Pancholi N, Bradner JE, You J: Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. J Virol 87(7): 3871-84, Apr 2013.

Wang X, Li J, Schowalter RM, Jiao J, Buck CB, You J: Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication. PLoS Pathogens 8(11): e1003021, 2012.

You J*, Wells SI: Human Papillomaviruses and Cancer. Cancer-Associated Viruses. Erle S. Robertson (eds.). Springer Press, 2012. (*corresponding author)

You J, Croyle JL, Nishimura A, Ozato K, Howley PM: Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell 117(3): 349-60, Apr 2004.

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Last updated: 09/01/2015
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