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Aging, Metabolism, Stress, Pathogenesis, and Small RNAs in C. elegans Topic Meeting 2012
Functions of MicroRNAs During Aging
Alexandre de Lencastre, Frank Slack
Yale University, New Haven, CT, USA
MicroRNAs (miRNAs) function to regulate gene expression during development in higher
eukaryotes. Previous work in our lab has demonstrated that miRNAs of previously unknown
function, such as miR-71, miR-238, miR-239 and miR-246 function during adulthood to promote
or antagonize longevity and stress response in C. elegans (1). We found that these miRNAs are
up-regulated in aging and genetically interact with components of the insulin signaling pathway
and the DNA damage checkpoint response pathway. Together with our previous observation
that mutations to the miRNA lin-4 and its target lin-14 significantly affect the lifespan of C.
elegans (2), these results establish miRNAs as a new class of aging-associated genes, with
the potential to interact with a wide range of aging pathways.
In order to understand the biological function of these age-associated miRNAs, we have
begun characterizing the factors downstream as well as upstream of these miRNAs that mediate
their function. We have shown by genetic epistasis that the insulin-signalling and the DNA
damage response pathways interact with miR-71 and miR-239. In order to characterize the
detailed molecular identities of pathway genes that may transduce these miRNAs’ functions,
we have surveyed the mRNA expression levels of multiple genes in these pathways in the
genetic background of aging-associated miRNA mutants. We have found significantly deregulated
expression of candidate targets genes in these pathways that are also predicted to
be direct targets of these miRNAs. Similarly, we have also begun characterizing the identity
of upstream factors that regulate the expression of our age-associated miRNAs. We have
evidence that suggests that 2 well-known transcription factors regulate the expression of specific
aging-associate miRNAs and suggest a possible function for these miRNAs as mediators of
organismal response to environmental stress. Given the high conservation of aging pathways
and miRNAs across species, it is likely that insights uncovered by this research will have high
relevance towards our understanding of aging in higher organisms and humans.
References:
1. de Lencastre A. et al., Curr Biol. 20, 1-10 (2010).
2. Boehm M., Slack FJ., Science. 310, 1954-7 (2005).
Contact: alexandre.delencastre@yale.edu
Lab: Slack
10
Session 2