An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans Cell 134, 291-303.
Yelena V. Budovskaya 1, Kendall Wu 1,3, Lucinda K. Southworth 2, Min Jiang 1, Patricia Tedesco 4, Thomas E. Johnson 4, Stuart K. Kim 1, 2, *

1 Department of Developmental Biology, Stanford University Medical Center, Stanford, California 94305, USA
2 Stanford Medical Informatics, Stanford University Medical Center, Stanford, California 94305, USA
3 Affymetrix, Inc., 3420 Central Expressway, Santa Clara, CA 95051
4 Department of Integrative Physiology, University of Colorado at Boulder, Box 447, Boulder, Colorado 80309, USA
* Corresponding author Stuart K. Kim, kim@cmgm.stanford.edu

Abstract

To define the C. elegans aging process at the molecular level, we used DNA microarray experiments to identify a set of 1294 age-regulated genes, and found that their upstream regions were enriched for GATA consensus DNA binding sites. We found that the GATA transcription factors ELT-3, ELT-5 and ELT-6 are responsible for age-regulation of a large fraction of these genes. Expression of elt-5 and elt-6 increases during normal aging and both of these GATA factors repress expression of elt-3, which shows a corresponding decrease in expression in old worms. elt-3 regulates a large number of downstream genes that change expression in old age including ugt-9, col-144 and sod-3. elt-5(RNAi) and elt-6(RNAi) worms have extended longevity, and elt-3 null mutants live shorter (in a genetic background that is long-lived), indicating that elt-3, elt-5 and elt-6 play an important functional role in the aging process. These results identify a novel transcriptional circuit that guides the rapid aging process in C. elegans, and indicates that this circuit is driven by drift of developmental pathways rather than accumulation of damage. This is a clear example of antagonistic pleiotropy as hypothesized by many pre-molecular theorists and provides an integrative view bringing the molecular and evolutionary views of aging to a mutual understanding.

 

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Figures

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Materials and Methods

Supplemental Tables

  1. Strains used in this study
  2. Aging microarray data (Excel file)
  3. 1254 age-regulated genes
  4. age-1 microarray data (Excel file)
  5. daf-16 (m26) microarray data (Excel file)
  6. Potential elt-3 GATA targets

Supplemental Figures

  1. Figure 1
  2. Figure 2