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

// Neeraj Kumar 1,2 , Vaibhav Jain 1,* , Anupama Singh 1,* , Urmila Jagtap 1 , Sonia Verma 1 and Arnab Mukhopadhyay 1 1 Molecular Aging Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India 2 Current address: Centre for Human Genetics and Molecular Medicine, School of Health Sciences , Central University of Punjab, Bathinda, India * These authors have contributed equally to this work Correspondence to: Neeraj Kumar, email: // Arnab Mukhopadhyay, email: // Keywords : DAF-16, FOXO, ChIP-seq, C. elegans, transcription, Gerotarget Received : August 31, 2015 Accepted : October 20, 2015 Published : November 02, 2015 Abstract 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.