Differential regulation of stress responses and lifespan by histone 3 lysine 4 (H3K4) methylation modifiers in Caenorhabditis elegans

Abstract

Mild forms of stress have been found to confer beneficial effects on lifespan of various model organisms. In Caenorhabditis elegans, mitochondrial dysfunction, disruption in the insulin/insulin-like signalling, and reduced protein translation have been documented to increase lifespan. This was proposed to be mediated through the activation of beneficial stress, immune, and detoxification responses. Recently, a modification associated with repression (H3K9 methylation) was found necessary for the mitochondrial stress response and longevity but it is unknown whether chromatin modifications associated with histone 3 lysine 4 (H3K4) methylations play a similar role. Therefore, the overall objective of this study was to investigate the role of H3K4 methylations, mediated by the COMPASS complex (Complex associated with SET1), in regulating stress responses and ageing. To study the effects of H3K4 methylations on long-lived mutants, worms lacking the COMPASS components RBBP-5 and WDR-5 were crossed with different longevity pathway mutants, including mitochondrial mutants (clk-1, isp-1), a protein translation mutant (ife-2), a mTOR pathway mutant (rsks-1) and an insulin-like pathway mutant (daf-2). Herein, we showed that WDR-5 and RBBP-5 contributed to post-embryonic growth and development. The loss of WDR-5 or RBBP-5 further delayed the already slow developing long-lived mutants in an additive manner. It was also demonstrated that WDR-5 or RBBP-5 are required for the mitochondrial unfolded protein response (UPRmt) but not heat or ER stress responses. We showed that RBBP-5 function was important for both natural and induced longevity, whilst WDR-5 was pathway specific. Overall, this research suggests that the mechanism underlying the role of RBBP-5 in longevity involves the coordination and expression of genes associated with lifespan, in particular genes associated with mitochondrial function.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Paul Shore (Supervisor), Alan Whitmarsh (Supervisor) & Gino Poulin (Supervisor)