UBC Theses and Dissertations
Comprehensive and integrative analysis of the KMT2D regulome Topham, James T.
Lysine (K)-specific methyltransferase 2D (KMT2D) is a critical component of epigenetic regulation through its role in mono-methylation of lysine 4 of histone H3 (H3K4me1). KMT2D is among the most frequently mutated genes in many forms of cancer, with particularly high occurrence of mutation in lymphoid malignancies. Despite being the recurrent target of somatic alteration across many cancer types, the consequences of KMT2D mutation, and their relevance to tumorigenesis, remain unclear. To expand on the current understanding of KMT2D loss, I performed comprehensive and integrative bioinformatics analyses of the epigenetic and transcriptome landscapes of isogenic KMT2D-mutant HEK293A cell lines. Analysis of ChIP-sequencing data from KMT2D-mutant cells showed genome-wide alterations in the distribution of H3K4me1, with loss of H3K4me1 occurring at active and poised enhancer regions. Interestingly, epigenetic disruption of enhancers in KMT2D-mutant cells was not sufficient for inducing transcriptional alteration of nearby genes, indicating a possible requirement for additional co-factors to be present in order to observe the consequences of KMT2D-dependent enhancer loss. Genes associated with KMT2D-dependent enhancers were enriched for members of the TGF-beta and retinoic acid (RA) signaling networks, highlighting transcriptional response to these pathways as candidate processes in which functional KMT2D-dependent enhancers may be required. Given the roles of both TGF-beta and RA signaling in cancer, identification of the convergence between the KMT2D regulome and these signaling axes provides a potential means by which KMT2D mutations may contribute to tumorigenesis.
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