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dc.contributor.advisorTarakhovsky, Alexander
dc.contributor.authorPark, Joon Seok
dc.description.abstractThe current view of signal transduction is that external stimuli trigger a series of cytosolic signaling events, which lead to the translocation of transcription factors, and changes in gene expression, which are dependent on the epigenetic landscape. Here, we discuss a paradoxical signaling paradigm in which a crucial chromatin modifier, Polycomb Repressive Complex 2 (PRC2), directly regulates receptor-proximal signaling. PRC2 catalyzes di/tri-methylation of histone 3 lysine 27 (H3K27me3), which correlates with transcriptional repression. While lysine methylation has largely been studied in the context of histone modification and epigenetic regulation, its role in the context of receptor-mediated signaling has rarely been described. In this study, we demonstrate that lysine methylation of cytosolic substrates by a cytosolic PRC2 complex plays an essential role in TCR-mediated T cell activation, independently from its nuclear function. Genetic ablation of essential PRC2 components in T cells had no effect on T cell development, loss of H3K27me3 or corresponding changes in gene expression. The resulting PRC2 deficient naïve T cells provided us with a good tool to study the signaling role of PRC2 in T cell activation, without an altered epigenetic landscape. These PRC2-deficient T cells fail to proliferate upon TCR stimulation in vitro and in vivo and PRC2-deficient T cells have a specific defect in TCR-induced Erk phosphorylation. Pharmacological inhibition of PRC2 further substantiated that PRC2 directly controls TCR signaling and the methyltransferase activity of PRC2 is required for TCR-induced Erk phosphorylation. To understand the mechanism(s) by which PRC2 controls TCR signaling, we examined the complex composition and identified cytosolic substrates of Ezh2. We found that cytosolic PRC2 (cPRC2) contains the core components of the nuclear PRC2 complex, indicating that its methyltransferase activity is present. Additionally we found that cPRC2 is associated with the TCR signaling components Vav1 and Nck1. We predicted Nck1 in silico as a PRC2 substrate by screening for target consensus-sequences among Vav1-interacting proteins. We show that Nck1 is methylated in vivo and Ezh2 is responsible for methylation of lysine 64 in Nck1 in vitro. In addition to Nck1, we also found Ezh2 is self-methylated, suggesting that cPRC2 may assemble a signaling complex through the methylation of several sites within the complex. This possibility was supported by data showing altered interactomes of Nck and Ezh2 upon inhibition of Ezh2 enzymatic activity. In summary, this study sheds light on an underappreciated role for lysine methylation of non-histone substrate by PRC2 in receptor-mediated signaling.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.subjectLysine methylation
dc.subjectPolycomb Repressive Complex 2
dc.subjectT cell
dc.subjectTCR signaling
dc.titleControl Of Tcr-Mediated T Cell Activation By Polycomb Repressive Complex 2
dc.typedissertation or thesis & Microbial Pathogenesis Cornell Graduate School of Medical Sciences of Philosophy

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