Main research interests:
- Global discovery of conserved genetic modules
- Functional genomics of human aging
- Functional genomics of C. elegans aging
- Global profiles of gene expression during development
Functional genomics of human aging (joint project with Stuart Kim, Developmental Biology and Art Owen, Statistics)
Functional genomics of C. elegans agingAging is a complex process driven by diverse molecular pathways and biochemical events. Our goal is to first identify genes that are differentially expressed in old versus young animals, and then to dissect apart how changes in these genes lead to functional decline and senescence in old age. We are using the nematode C. elegans as a model system for aging, because it has a rapid lifespan, a small size, a powerful genetic toolkit and many mutants are already known to lengthen lifespan.
We have used DNA microarrays to perform a genome-wide screen for genes that change expression in old worms, in the dauer state (an alternative stage with an extremely long lifespan), and in four mutants with altered lifespans. We combined the expression results from these DNA microarray experiments and identified a core set of 233 genes that show consistent changes in expression across different aging experiments. Interestingly, this set of genes may be regulated by a GATA factor transcriptional circuit, as it is enriched for genes that contain a GATA motif in their upstream regions, and one of the age-regulated genes (med-1) encodes a GATA transcription factor.
Having identified age-regulated genes, we propose to study the function of
a large number of these genes in parallel, to reveal underlying mechanisms in
the process of aging. Specifically, we will generate GFP reporters for the age-regulated
genes in order to use them as biomarkers for age and to reveal which tissues
are most susceptible to age-related decline. We will use loss- and gain-of-function
experiments to elucidate the function of these genes on aging. Finally, we will
elucidate how a GATA transcriptional circuit controls aging, and perform a genome-wide
RNAi screen for new aging mutants.
Global profiles of gene expression during development
We are using DNA microarrays containing nearly every gene in the C. elegans genome to determine which genes are expressed in the major tissues of the adult hermaphrodite. We use a new method called mRNA tagging to identify most or all of the genes expressed in muscle cells, neurons, skin epithelia, intestinal cells and the vulval precursor cells. We can use the global survey of gene expression in C. elegans development to study entire networks of genes that specify the major tissues. How similar are different tissues to each other? Does gene expression reflect where the tissue comes from (endoderm vs ectoderm) or the tissue type (epithelial vs mesenchymal)? Can we find evidence for long-range control of gene expression, possibly due to chromatin domains or locus controlling elements?
Last modified 6/27/2005
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