Genome-wide endogenous DAF-16/FOXO recruitment dynamics during lowered insulin signalling in C. elegans

• Published in: Oncotarget 2015-12, Vol.6 (39), p.41418-41433
• Main Authors: Kumar, Neeraj, Jain, Vaibhav, Singh, Anupama, Jagtap, Urmila, Verma, Sonia, Mukhopadhyay, Arnab
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Chromatin Assembly and Disassembly; Chromatin Immunoprecipitation; Computational Biology; Databases, Genetic; Down-Regulation; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Genotype; Insulin - metabolism; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; Promoter Regions, Genetic; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Research Paper: Gerotarget (Focus on Aging); Signal Transduction; Transcription, Genetic; Transcriptional Activation
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6282

Lowering insulin-IGF-1-like signalling (IIS) activates FOXO transcription factors (TF) to extend life span across species. To study the dynamics of FOXO chromatin occupancy under this condition in C. elegans, we report the first recruitment profile of endogenous DAF-16 and show that the response is conserved. DAF-16 predominantly acts as a transcriptional activator and binding within the 0.5 kb promoter-proximal region results in maximum induction of downstream targets that code for proteins involved in detoxification and longevity. Interestingly, genes that are activated under low IIS already have higher DAF-16 recruited to their promoters in WT. DAF-16 binds to variants of the FOXO consensus sequence in the promoter proximal regions of genes that are exclusively targeted during low IIS. We also define a set of 'core' direct targets, after comparing multiple studies, which tend to co-express and contribute robustly towards IIS-associated phenotypes. Additionally, we show that nuclear hormone receptor DAF-12 as well as zinc-finger TF EOR-1 may bind DNA in close proximity to DAF-16 and distinct TF classes that are direct targets of DAF-16 may be instrumental in regulating its indirect targets. Together, our study provides fundamental insights into the transcriptional biology of FOXO/DAF-16 and gene regulation downstream of the IIS pathway.