Abstract The University of Manchester Adriana Raluca Vintila PhD Molecular Biology The Role of Histone 3 Lysine 4 Methylation in Ageing and Stress Resistance 2017 Ageing, the accumulation of changes leading to decline of function occurring over the lifetime of an organism, is the single biggest risk factor for age related diseases. Ageing is determined by genetic and epigenetic factors, as well as metabolism and sensory perception. However, the exact mechanism of ageing remains largely unknown. Interventions that slow down ageing, also delay the onset of age related diseases and increase stress resistance. The Set/COMPASS complex, which has been conserved from yeast to humans, is involved in histone 3 lysine 4 methylation (H3K4me). This complex is composed of the methyltransferases, SET-2 and SET-16, and of the non-enzymatic core components, ASH-2, RBBP-5, WDR-5, which are involved in complex stability. Depletion of SET-2, ASH-2 and WDR-5 extends lifespan and decreases H3K4me levels. In this study, I have shown that deletion of another member of the core complex, RBBP-5, shortens lifespan. Furthermore, I have shown that under mitochondrial stress conditions, RBBP-5 acts as an attenuator of the mitochondrial unfolded protein response (UPRmt) for which it requires SEC-12, a guanine nucleotide exchange factor essential for transport vesicle budding from the endoplasmic reticulum. Next, I conducted gene ontology analysis on differentially regulated genes in these mutants and found that sensory perception is a misregulated biological process. To test if sensory perception is skewed in the absence of WDR-5 or RBBP-5, I exposed mutant worms to a variety of acute environmental stresses and showed that they are generally more resistant to stress as compared to wild-type worms. Finally, because tissues such as neurons and the intestine are crucial for sensory perception, I created a spatial and temporal gene expression toolkit. This can be used to study the tissue or developmental stage in which WDR-5 or RBBP-5 are required for lifespan, sensory perception and stress regulation. I propose that RBBP-5 may act as an attenuator of ageing, delaying death.
|Date of Award||1 Aug 2018|
- The University of Manchester
|Supervisor||Chris Knight (Supervisor) & Gino Poulin (Supervisor)|