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.
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.
|Chang, Hsin-Wen; Shtessel, Ludmila; Lee, Siu Sylvia (2015) Collaboration between mitochondria and the nucleus is key to long life in Caenorhabditis elegans. Free Radic Biol Med 78:168-78|
|Jin, Yue; Shenoy, Anitha K; Doernberg, Samuel et al. (2015) FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development. Cancer Lett 362:70-82|
|Pu, Mintie; Ni, Zhuoyu; Wang, Minghui et al. (2015) Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. Genes Dev 29:718-31|
|Baruah, Aiswarya; Chang, Hsinwen; Hall, Mathew et al. (2014) CEP-1, the Caenorhabditis elegans p53 homolog, mediates opposing longevity outcomes in mitochondrial electron transport chain mutants. PLoS Genet 10:e1004097|
|Hwang, Ara B; Ryu, Eun-A; Artan, Murat et al. (2014) Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans. Proc Natl Acad Sci U S A 111:E4458-67|
|Iwata, Terri N; Cowley, Timothy J; Sloma, Michael et al. (2013) The transcriptional co-regulator HCF-1 is required for INS-1 Î²-cell glucose-stimulated insulin secretion. PLoS One 8:e78841|
|Lee, Siu Sylvia; Schroeder, Frank C (2012) Steroids as central regulators of organismal development and lifespan. PLoS Biol 10:e1001307|
|Rizki, Gizem; Picard, Colette Lafontaine; Pereyra, Charles et al. (2012) Host cell factor 1 inhibits SKN-1 to modulate oxidative stress responses in Caenorhabditis elegans. Aging Cell 11:717-21|
|Ni, Zhuoyu; Ebata, Atsushi; Alipanahiramandi, Elham et al. (2012) Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. Aging Cell 11:315-25|
|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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