The role of epigenetics in transcriptional stochasticity and the implications for breast cancer drug resistance

Even under the most extreme regulatory constraints, the process of gene transcription is inherently noisy, producing variance in transcriptional output across isogenic populations of cells. While frequently overlooked, this variance in gene expression can have significant consequences for developmental processes, phenotypic divergence and emergence, and ultimately survival of unicellular or multicellular organisms. In no biological context is this more relevant than in that of cancer, where transcriptional heterogeneity predicts poor prognosis and the development of resistance to therapeutics. Recent advances in our understanding of transcription at single cell resolution suggests that a large proportion of gene expression noise originates from the stochastic nature of promoter activity and gene transcription, yet there are currently no methods for full quantification of transcriptional kinetics at a genome-wide scale. Furthermore, how epigenetics impinges upon gene activity within this context of transcriptional stochasticity remains largely unknown, with most studies to date focussing on specific genomic loci in a low throughput manner. In this thesis I aim to further understanding of transcriptional kinetics and their epigenetic foundations by first discussing the current consensus, followed by the presentation of a novel approach that allows for full transcriptional characterisation in MCF-7 breast cancer cells. This reveals several genetically and epigenetically encoded mechanisms of transcriptional stochasticity. Subsequently, I investigate the impact of various temporally acute modes of epigenetic interference on transcriptional dynamics and suggest the clinical significance of the findings.