Association of caspase-mediated cell death and Epstein-Barr virus lytic reactivation
Dr. Chon Phin Ong (Post-doctoral Fellow)
[Supervisor: Professor Dong-Yan Jin]

Epstein-Barr virus, or human herpesvirus 4 is known as an oncogenic virus. EBV often targets B-lymphocyte and epithelial cells, often establishing lifelong latency infection in host cells. Several viral proteins, expressing at different latency stages as well as lytic cycle to facilitate cellular proliferation, evade apoptosis and inhibited host immune surveillance. Here, we show that caspase-mediated cell death induced by chemotherapeutic drug, 5-FU could induce Epstein-Barr virus lytic reactivation through the activation of p53 pathway. Subsequent analysis revealed downregulation of IFITM2 protein, a commonly known interferon-induced antiviral protein to facilitate viral replication. Understanding the latent-lytic switch mechanism will expedite formulation of prophylactic vaccines and antiviral strategies against Epstein-Barr virus.

Decoding how the re-design of the pioneer factor KLF4 directs epigenetic reprogramming
Dr. Yanmin Zhang (Post-doctoral Fellow)
[Supervisor: Professor Ralf Jauch]

Re-engineering pioneer transcription factors can help develop designer proteins that enable reprogramming technologies for genomic medicine. epigenetic rejuvenation and biotechnical approaches for wildlife conservation. We recently identified KLF4 variants (eKLF4) with re-engineered methylation and base reader interface that can support the induction of pluripotent stem cells (iPSCs) without SOX2 or OCT4. To understand how eKLF4 rewires the epigenome, we integrated genome-wide chromatin accessibility, DNA methylation, and binding profiles. We found that eKLF4 exhibits altered DNA sequence preferences relative to wild type KLF4, which redirects its genome wide binding, enhances its binding to methylated DNA and facilitating chromatin opening. eKLF4 enhances activation of epithelial and pluripotency programs, dampens a deleterious inflammatory response, and enables reprogramming with a minimalist two-factor cocktail. Leveraging these enhanced capabilities, we are now applying engineered pioneer factors to overcome species-specific barriers to pluripotency reprogramming, using blood and urine samples from dolphins at Hong Kong Ocean Park. Broadly, this work establishes design principles for manipulating cell states and could lead to stem cell biotechnologies for genetic rescue and wildlife conservation.

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