DamID in C. elegans reveals longevity-associated targets of DAF-16/FoxO.
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.
Schuster
Eugene
E
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK. e.schuster@ucl.ac.uk
McElwee
Joshua J
JJ
Tullet
Jennifer M A
JM
Doonan
Ryan
R
Matthijssens
Filip
F
Reece-Hoyes
John S
JS
Hope
Ian A
IA
Vanfleteren
Jacques R
JR
Thornton
Janet M
JM
Gems
David
D
D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods*; D018507:Gene Expression Regulation, Developmental; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D002843:Chromatin; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)