Transcription factors of the DAF-16/FOXO family are evolutionarily conserved master regulators capable of integrating diverse environmental stimuli and coordinating development, metabolism, stress responses, and longevity. Deregulation of FOXO proteins in humans is well known to play a key role in age- related diseases such as cancer and diabetes. For DAF-16/FOXOs to achieve their multi-faceted and central roles, their transcriptional activities need to be exquisitely regulated;however, the mechanisms underlying the regulation of DAF-16/FOXO-mediated gene transcription are largely unknown. The long-term goal of this proposal is to elucidate comprehensively how DAF-16/FOXO transcriptional activities are regulated in the nucleus and how this regulation contributes to longevity determination. We recently discovered that the C. elegans ortholog of the nuclear protein host cell factor 1 (HCF-1) modulates longevity by functioning as a DAF-16 co-factor that inhibits DAF-16-mediated gene regulation. Since HCF-1 is the first DAF-16 negative co-factor reported in C. elegans, this finding provides an important entry point for further investigation of how DAF-16 transcriptional activities are regulated.
In Aim 1, we propose to test the hypothesis that the specificity of DAF-16-mediated transcriptional output is determined by the interplay between HCF-1 and other DAF-16 co-factors.
In Aim 2, we propose to test the hypothesis that HCF-1 forms a regulatory network with SIR-2.1 to regulate DAF-16 transcriptional activity on specific target genes.
In Aim 3, we propose to identify additional transcription and chromatin factors that regulate DAF-16-mediated gene transcription. Since DAF-16 and its co-factors (HCF-1, SIR-2.1, SMK-1, BAR-1, CTBP-1) are all highly conserved, findings from our studies will provide important insights into FOXO regulation and longevity determination in mammals. Moreover, the mammalian orthologs of DAF-16 and its co-factors are known to play key roles in the pathogenesis of a number of human diseases, such as cancer and diabetes, findings from our studies may inspire future therapeutic development aiming to alleviate some of these age-related pathologies in humans.

Public Health Relevance

Transcription factors of the DAF-16/FOXO family are highly conserved master regulators capable of integrating diverse environmental stimuli and coordinating development, metabolism, stress responses, and longevity. This application proposes to use the powerful genetic model C. elegans to investigate how several highly conserved DAF-16 co-factors function together to precisely control DAF-16-mediated gene regulation. The findings from this proposal will have direct relevance to FOXO regulation in mammals and will provide important insights into the biology of aging, and may inspire future therapeutic development that aims to benefit longevity and alleviate age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024425-08
Application #
8305535
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2004-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$302,132
Indirect Cost
$105,086
Name
Cornell University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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Rizki, Gizem; Iwata, Terri Naoko; Li, Ji et al. (2011) The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet 7:e1002235

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