WDR5 is a Conserved Regulator of Protein Synthesis Gene Expression

Abstract

WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. Efforts to better understand WDR5 have been complicated by its many functions in the nucleus, and thwarted by a lack of knowledge of the conserved gene networks that are under its control. This dissertation will provide a succinct history of WDR5, followed by the results of comparative genomic analyses performed across a diverse panel of cancer cell lines, and a discussion reflecting on what the reported experiments indicate about the biological function of WDR5, as well as the future of WDR5 research. Genomic analysis of WDR5 was executed in order to identify the conserved sites of WDR5 binding to chromatin and the conserved genes regulated by WDR5, regardless of cell type or species. These experiments show that a specific cohort of protein synthesis genes are consistently bound by WDR5, demonstrate that the WIN site of WDR5 anchors WDR5 to chromatin at these sites, and establish that protein synthesis genes are both acute and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant and conserved role in the transcription of ribosome protein genes, and forecast that inhibition of WDR5 via novel WIN site inhibitors may prove to be clinically viable, effectively disrupting protein synthesis and ribosome protein subunit homeostasis.