Year: 2021
Type: dissertation
Abstract: Regulatory variation in gene expression not only allows for phenotypic diversity that shapes developmental complexity and morphogenesis, but is also a fundamental mechanism behind adaptation and the evolution of complex traits.Transcriptional regulation is achieved through the interlinked activities of a multitude of hierarchical regulators at different levels; chromatin modifiers, transcription factors, non-coding RNAs and various post-transcriptional processes.Whilst not necessarily apparent in normal physiological settings, regulatory variations and perturbations are associated with the development of many complex diseases.The limited understanding of the scope and significance of lesser-characterised regulators, such as non-coding RNAs, has made causally linking these variants with gene expression changes that underpin the aetiology of disease a significant hurdle to overcome.Consequently, the aim of this thesis was to identify and characterise novel and key regulators of gene expression in endothelial cells exposed to acute hypoxia.Through the combined use of nascent and steady-state transcriptomic approaches, we could identify ~300 genes differentially expressed as a consequence of hypoxia.Unlike most other cell types, hypoxia was seen to generally increase the transcriptional output of endothelial cells.Modelling of nascent and steady-state RNA dynamics revealed that these changes occurred as a result of increased rates of transcription, rather than changes in rates of RNA processing or decay.Induction of transcription occurred through combined de novo RNA polymerase II loading and promoter-proximal pause release.Conversely, inhibition was caused through induced pausing, the combination of which resulted in a global increase in 5' gene transcription.The majority of the differentially expressed hypoxic transcriptome Annakaisa, I will forever be grateful for the years of support and understanding.
Author: Nicholas Downes
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3206466348