Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Neeraj Kumar _, Vaibhav Jain, Anupama Singh, Urmila Jagtap, Sonia Verma and Arnab Mukhopadhyay

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Oncotarget. 2015; 6:41418-41433. https://doi.org/10.18632/oncotarget.6282

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Abstract

Neeraj Kumar1,2, Vaibhav Jain1,*, Anupama Singh1,*, Urmila Jagtap1, Sonia Verma1 and Arnab Mukhopadhyay1

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.


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