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Title: Chromatin regulation of lifespan in C. elegans
Author: Chocian, Karolina
ISNI:       0000 0004 6353 0818
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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The biological basis of lifespan regulation is a subject of intense interest, and epigenetic control of gene expression is thought to play an important role in the ageing process. A library of RNAi clones against chromatin factors was used to screen for their effects on lifespan in C.elegans, utilising microscopic examination of lipofuscin accumulation as a primary biomarker of ageing. A secondary RNAi screen involving full lifespan monitoring confirmed knock-downs of four genes, isw-1, cbp-1, mes-2 and jmjd-3.2, results in extension of lifespan. The use of mutant alleles of these genes also resulted in statistically significant lifespan extension. Intriguingly, three of those genes encode H3K27 modifiers: cbp-1 is an acetyl transferase, whilst mes-2 and jmjd-3.2 are H3K27 methyltransferase and demethylase respectively. Mutation in another gene of the jmjd-3.2 family, utx-1, is also known to have a lifespan prolonging effects by increasing H3K27 methylation on the daf-2 promoter (Jin et al, 2012). In addition to its lifespan effects, utx-1 is also an essential developmental gene. Its role in development has, however, been confirmed to be independent of its demethylase activity (Vandamme et al. 2012) raising questions about the biological significance of UTX-1- mediated H3K27 demethylation. I used a demethylase-dead form of UTX-1 to demonstrate that enzymatic activity is absolutely required for UTX-1 function in lifespan regulation. Intriguingly, it is not just utx-1 loss of function that causes lifespan extension; overexpression of utx-1 from a transgenic array is associated with even more dramatic lifespan extension. Moreover, mes-2 and jmjd-3.2 overexpression also increases the lifespan of transgenic animals. Interestingly, however, lifespan extension driven by overexpression of jmjd-3.2 is not dependent on its demethylase function, suggesting a different mode of action to utx-1. Epistasis analysis suggests that the insulin signalling pathway is a crucial target of regulation for all the factors I identified, but ChIP analysis implies that lifespan extension driven by utx-1 overexpression may involve a different pathway from H3K27me3 regulation at the daf-2 locus. Overall, this work pinpoints H3K27 modifications at key target genes as critical determinants of longevity, and furthermore identifies the crucial importance of the fine balance of factors controlling H3K27 methylation status.
Supervisor: Woollard, Alison ; Mellor, Jane Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available