Other projects:

Project 2

Project 3

Project 4

fig1

Figure 1: Novel miRNAs Identified in Aged C. elegans. Secondary structures of putative precursor hairpins corresponding to miRNAs identified in a pool of RNAs enriched for aged C. elegans. The predicted mature sequences are highlighted in red. (de Lencastre, Current Biology, 2010)

Project 1:

Novel miRNA regulators of aging

Studies pioneered in C. elegans have demonstrated that lifespan is surprisingly plastic and is influenced by a complex interplay of genetic mechanisms that respond to stress, nutrient availability and environment. We have used deep sequencing to identify 10 novel miRNAs that are expressed in aged C. elegans (Fig.1) and to show that several of the most highly up-regulated miRNAs in aging affect lifespan and stress resistance (Fig. 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. Given how little is known about miRNAs and aging, this area of research appears to be a largely unexplored field with great potential for innovation and biological discovery. Our lab aims to characterize the function of known and novel miRNAs during adulthood in C. elegans by characterizing their roles on longevity, stress resistance and neurodegenerative pathologies, such as Alzheimer’s, Parkinson’s and Huntington’s (see Project 2). In order to test whether novel miRNAs have an active function on aging in C. elegans our lab is currently obtaining or generating mutants of these miRNAs from the CGC (C. elegans Genetics Consortium) and test their lifespan, stress resistance and other associated phenotypes. Novel miRNAs that exhibit interesting aging or stress-associated phenotypes will then be further characterized for potential downstream targets (see also Project 3).

Fig2

Figure 2: Deletion or Overexpression of Aging-Associated miRNAs affects lifespan in C. elegans. Four miRNA genes that are among the most overexpressed in aged animals—mir-71, mir-238, mir-239, and mir-246—exhibit significant changes in life span when mutated. C. elegans mutants that contain deletions of miR-71, miR-238, and miR-246 — mir-71(n4115) (red), mir-238(n4112) (blue), and mir-246(n4636) (magenta)—exhibit significantly reduced life span compared to wild-type (N2) animals (black), whereas deletion of miR-239—mir-239(nDf62) (green)—extends life span.

Stress Resistance in miRNA Mutants Correlates with Their Life-Span Phenotypes. mir-71(n4115) mutants have extreme sensitivity to environmental stress, consistent with their dramatically shortened lifespan.

miR-71 overexpression extends life span - confirming that miR-71 promotes longevity in C. elegans. Three lines overexpressing (o/e) miR-71 exhibit longer life spans compared to wild-type N2 animals. (de Lencastre, Current Biology, 2010)