Inflammation associated modulation of DNA methylation: An investigation into the genetic determinants and transcriptional consequences (360G-Wellcome-201488_Z_16_Z)

Chronic inflammation is pathologically and genetically implicated in conditions as diverse as Alzheimer’s disease and cancer. DNA methylation helps determine cellular activity and is frequently aberrant in malignancies. Given methylation is sensitive to the environment, understanding the effects of immune activity whilst considering genotype is of high importance. This application proposes to develop unpublished data where I observe stimulation with Toll-like receptor agonists leads to significant, highly delineated, genome-wide changes in monocyte DNA methylation in a genotype dependent manner. Notably, genes frequently mutated in cancer are enriched amongst those displaying immune triggered demethylation, suggesting a direct link between inflammation and mutagenic pressure. I will characterize the pathophysiological importance of these observations by describing the kinetics of differential methylation and describing the effects on gene expression. I will investigate how the local chromatin environment is influenced by changes in DNA methylation using ChIP-seq to histone and TET proteins. I further aim to explore whether changes in methylation are detectable at the single cell level. By developing a comprehensive panel of inflammation sensitive methylation sites I will explore whether these changes can be observed in clinical samples from cancer and infection, furthering our understanding of how past inflammatory events modify future responses.