Transcriptome Analysis of Insulin Signaling-Associated Transcription Factors in C. elegans Reveal Their Genome-Wide Target Genes Specificity and Complexity

Abstract

first_pageDownload PDFsettingsOrder Article Reprints Open AccessArticle Transcriptome Analysis of Insulin Signaling-Associated Transcription Factors in C. elegans Reveal Their Genome-Wide Target Genes Specificity and Complexity by Neha Kaushik 1,Soumya Rastogi 1,Sonia Verma 2ORCID,Deepak Pandey 1ORCID,Ashutosh Halder 1ORCID,Arnab Mukhopadhyay 3ORCID andNeeraj Kumar 1,*ORCID 1 Department of Reproductive Biology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India 2 Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India 3 Molecular Aging Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India * Author to whom correspondence should be addressed. Int. J. Mol. Sci. 2021, 22(22), 12462; https://doi.org/10.3390/ijms222212462 Submission received: 12 October 2021 / Revised: 8 November 2021 / Accepted: 9 November 2021 / Published: 18 November 2021 (This article belongs to the Special Issue Genetics and Epigenetics of Aging and Longevity 2.0) Downloadkeyboard_arrow_down Browse Figures Versions Notes Abstract Insulin/IGF-1-like signaling (IIS) plays a crucial, conserved role in development, growth, reproduction, stress tolerance, and longevity. In Caenorhabditis elegans, the enhanced longevity under reduced insulin signaling (rIIS) is primarily regulated by the transcription factors (TFs) DAF-16/FOXO, SKN-1/Nrf-1, and HSF1/HSF-1. The specific and coordinated regulation of gene expression by these TFs under rIIS has not been comprehensively elucidated. Here, using RNA-sequencing analysis, we report a systematic study of the complexity of TF-dependent target gene interactions during rIIS under analogous genetic and experimental conditions. We found that DAF-16 regulates only a fraction of the C. elegans transcriptome but controls a large set of genes under rIIS; SKN-1 and HSF-1 show the opposite trend. Both of the latter TFs function as activators and repressors to a similar extent, while DAF-16 is predominantly an activator. For expression of the genes commonly regulated by TFs under rIIS conditions, DAF-16 is the principal determining factor, dominating over the other two TFs, irrespective of whether they activate or repress these genes. The functional annotations and regulatory networks presented in this study provide novel insights into the complexity of the gene regulatory networks downstream of the IIS pathway that controls diverse phenotypes, including longevity.