Cellular Reprogramming in Response to Viral Infection and Oncogenic Transformation

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2021

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In this dissertation, I reported several cellular reprogramming mechanisms in response to different factors, such as viral infection and oncogenic transformation, by utilizing molecular biology and high-throughput sequencing tools. In the first part of the dissertation, I investigated how hepatocytes contain HBV replication and promote their own survival by orchestrating a translational defense mechanism via the stress-sensitive SUMO-2/3-specific peptidase SENP3. We found that SENP3 expression level decreased in HBV-infected hepatocytes in various models including HepG2-NTCP cell lines and a humanized mouse model. Downregulation of SENP3 reduced HBV replication and boosted host protein translation. We also discovered that IQGAP2, a Ras GTPase-activating-like protein, is a key substrate for SENP3-mediated de-SUMOylation. Downregulation of SENP3 in HBV infected cells facilitated IQGAP2 SUMOylation and degradation, which leads to suppression of HBV gene expression and restoration of global translation of host genes via modulation of AKT phosphorylation. In the second part, I showed that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. I identified two orthogonal processes in Kras-mutant distal airway club cells. The first process was step-like in behavior and promoted their trans-differentiation into an AEC2-like state through NKX2.1. The second was linear and controlled oncogenic transformation through the AP-1 complex. Our results suggest that the chromatin state of the cell influences its response to oncogenic Kras. Other than the cell-type-specific effects, a cross-tissue conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.

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Xi, Rui (2021). Cellular Reprogramming in Response to Viral Infection and Oncogenic Transformation. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/23765.

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