Wilson, Thomas Stuart; (2023) Investigating robustness of the epigenetic regulatory network. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The molecular control of epigenetic information is highly complex, involving hundreds of regulatory components, pathways, and complexes that regulate chromatin structure and epigenetic landscapes. This complexity maintains robust outputs from the diverse genome functions controlled by the epigenetic regulatory network (ERN) across fluctuating conditions and perturbations. The function of many components has been characterised, but how different layers of epigenetic regulation interact, and how they are integrated into a robust regulatory network, remains poorly understood. Here, using systematic genetic perturbation of hundreds of epigenetic regulators, I show that most individual epigenetic regulators are dispensable in the ERN of non-tumorigenic human cells. The network is broadly robust to mutation, and this emerges from multiple layers of functional redundancy and degeneracy. By combining perturbations, I explore the contribution of paralogues to robustness and reveal maps of functional interactions within the ERN across epigenetic regulatory classes. I also explore the cumulative epigenetic disruption associated with combined regulator loss and oncogene activation, finding that accumulated disruption sensitises cells to further perturbation and reveals a synthetic fragility of the network. Overall, this study explores the robustness of the ERN, examines how it emerges through interactions between redundant and degenerate components, and reveals how these properties change as the epigenome is progressively dysregulated in disease.

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