Abstract
In Caenorhabditis elegans, the six proteins that make up the REF-1 family have been identified as functional homologs of the Hairy/Enhancer of Split (HES) proteins. These transcription factors act in both Notch dependent and Notch-independent pathways to regulate embryonic events during development; however, their post-embryonic functions are not well defined. As a first step toward understanding how the REF-1 family works together to coordinate post-embryonic events, we used gene expression microarray analysis to identify transcriptional targets of HLH-29 in L4/young adult stage animals. Here we show that HLH-29 targets are genes needed for the regulation of growth and lifespan, including genes required for oxidative stress response and fatty acid metabolism, and the ferritin genes, ftn-1 and ftn-2. We show that HLH-29 regulates ftn-1 expression via promoter sequences upstream of the iron-dependent element that is recognized by the hypoxia inducible factor, HIF-1. Additionally, hlh-29 mutants are more resistant to peroxide stress than wild-type animals and ftn-1(RNAi) animals, even in the presence of excess iron. Finally we show that HLH-29 acts parallel to DAF-16 but upstream of the microphthalmia transcription factor ortholog, HLH-30, to regulate ftn-1 expression under normal growth conditions.
Highlights
The Hairy/Enhancer of Split (HES) transcription factors, members of the basic Helix-Loop-Helix superfamily, coordinate cellular and environmental signals to direct cellular proliferation and tissue morphogenesis
In young adult animals, the network includes genes involved in regulating iron homeostasis, fatty acid metabolism, and oxidative stress response, many of which are co-expressed with hlh29 in the intestine
We show that many HLH-29 targets are targets of DAF-16, the insulin/IGF-1 signaling transcription factor that integrates multiple pathways to control lifespan, stress response, and fat storage
Summary
The Hairy/Enhancer of Split (HES) transcription factors, members of the basic Helix-Loop-Helix (bHLH) superfamily, coordinate cellular and environmental signals to direct cellular proliferation and tissue morphogenesis. Through physical interactions with multiple classes of transcription factors and transcriptional co-repressors, HES proteins regulate a large number and variety of target genes [1,2,3,4] that are critical for both embryonic development and homeostasis in the adult. In Caenorhabditis elegans, the six proteins that make up the REF-1 family have been identified as functional homologs of the HES proteins. Like the HES proteins, members of the REF-1 family are all involved in embryonic Notch/ligand interactions [10,11,12], they all appear to regulate specification and development of the mesoderm and endoderm [13,14], and they act in both Notch-dependent and Notchindependent functions [15,16,17]. Though the REF-1 family lacks the Orange domain that is common to HES proteins in all other organisms, it is possible that the second bHLH domain found in members of the REF-1 family functionally substitutes for the Orange domain to facilitate and stabilize protein-protein interactions
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