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UBC Theses and Dissertations

Transcriptional silencing of endogenous retroviruses by the novel lysine methyltransferase co-repressor hnRNP K Thompson, Peter Jeffrey


Histone lysine methylation is essential for mammalian development and maintenance of somatic cell identity, as evidenced by a group of Mendelian diseases and cancers linked with mutations in lysine methyltransferases (KMTs). The transcriptional silencing of a class of retrotransposons known as endogenous retroviruses (ERVs) in murine embryonic stem cells (mESCs) provides a unique model system in which to investigate epigenetic regulation by the H3K9 family of KMTs and characterize novel molecular mechanisms of relevance to human biology and disease. In mESCs, class I and II ERVs are silenced by the SETDB1/KAP1 complex, which deposits histone H3K9 trimethylation (H3K9me3). In contrast, class III MERVL ERVs are silenced by the G9a/ GLP complex, which deposits H3K9me2. The molecular mechanisms governing the recruitment of these KMTs to their genomic ERV targets remain poorly understood. The goal of this work was to identify and characterize novel factors that regulate the functions of these KMTs in ERV silencing. In the first part of my thesis work, I identified the RNA-binding protein and transcription factor hnRNP K as a novel co-repressor for the SETDB1/KAP1 complex. HnRNP K coordinates recruitment of the KMT SETDB1 by KAP1 to its ERV targets. This function of hnRNP K involves a previously uncharacterized influence on the levels of chromatin protein SUMOylation. In the second part of my thesis work, I demonstrated that MERVL elements are also repressed by hnRNP K and can remain inactive in the absence of H3K9me2, likely due to the lack of transcriptional activators. HnRNP K forms a novel RNA-dependent complex with G9a/GLP, is required for global H3K9me2 and provides a repressive barrier to MERVL expression in the presence and absence of H3K9me2. Taken together my work has provided significant insights into the epigenetic repression of ERV transcription by KMTs and demonstrates that hnRNP K is a novel co-repressor for two different KMT complexes. As recent studies have linked mutations in HNRNPK to the novel Mendelian disorder Au-Kline syndrome and cancer, these insights should also guide future studies on the role of hnRNP K in regulation of KMT-mediated signaling pathways in human disease.

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