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)


We propose to elucidate mechanisms of human aging at the molecular level. Recently, several laboratories including our own have taken a powerful approach to understanding molecular changes associated with age, which is to use DNA microarrays or DNA chips to profile gene expression changes during an organisms lifetime across the entire genome. These studies have generated molecular profiles of aging in model organisms such as worm, flies and mice. It is now crucial to extend these studies to human aging because model organisms age much more rapidly than humans, and therefore the precise mechanisms of human aging may be different. We are using the kidney to study human aging because this organ shows a strong decline in function with age.

Our first goal is to generate a molecular profile showing how nearly every gene is expressed in the kidney with respect to age. We have already collected 74 kidneys from patients ranging in age from 27 to 92 years. We will use Affymetrix DNA chips to profile expression levels from each of these kidneys, thereby forming a genome-wide time course for aging in the kidney. Our preliminary analysis of analysis of genes from only half of the genome shows 215 aging regulated genes. These are the first molecular markers for human aging in the kidney, and analysis of the rest of the genome will certainly elucidate more biomarkers for aging.

Functional genomics of C. elegans aging

Aging 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

Please send comments or questions regarding this home page to Yong J. Chong (yjchong@stanford.edu)