DamID in C. elegans reveals longevity-associated targets of DAF-16/FoxO

Mol Syst Biol. 2010 Aug 10;6:399. doi: 10.1038/msb.2010.54.

Abstract

Insulin/IGF-1 signaling controls metabolism, stress resistance and aging in Caenorhabditis elegans by regulating the activity of the DAF-16/FoxO transcription factor (TF). However, the function of DAF-16 and the topology of the transcriptional network that it crowns remain unclear. Using chromatin profiling by DNA adenine methyltransferase identification (DamID), we identified 907 genes that are bound by DAF-16. These were enriched for genes showing DAF-16-dependent upregulation in long-lived daf-2 insulin/IGF-1 receptor mutants (P=1.4e(-11)). Cross-referencing DAF-16 targets with these upregulated genes (daf-2 versus daf-16; daf-2) identified 65 genes that were DAF-16 regulatory targets. These 65 were enriched for signaling genes, including known determinants of longevity, but not for genes specifying somatic maintenance functions (e.g. detoxification, repair). This suggests that DAF-16 acts within a relatively small transcriptional subnetwork activating (but not suppressing) other regulators of stress resistance and aging, rather than directly regulating terminal effectors of longevity. For most genes bound by DAF-16::DAM, transcriptional regulation by DAF-16 was not detected, perhaps reflecting transcriptionally non-functional TF 'parking sites'. This study demonstrates the efficacy of DamID for chromatin profiling in C. elegans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Chromatin / metabolism
  • DNA Methylation
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Developmental
  • Longevity / genetics
  • Longevity / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Site-Specific DNA-Methyltransferase (Adenine-Specific) / metabolism*
  • Transcription Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Chromatin
  • Forkhead Transcription Factors
  • RNA, Messenger
  • Transcription Factors
  • daf-16 protein, C elegans
  • Site-Specific DNA-Methyltransferase (Adenine-Specific)