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SESN3  has been implicated in multiple biological processes including protection against oxidative stress, regulation of glucose and lipid metabolism. However, little is known about the factors and mechanisms controlling its gene expression at the transcriptional level. We performed in silico phylogenetic footprinting analysis of 5 kb upstream regions of a diverse set of human  SESN3  orthologs for the identification of high confidence conserved binding motifs (BMo). We further analyzed the predicted BMo by a motif comparison tool to identify the TFs likely to bind these discovered motifs. Predicted TFs were then integrated with experimentally known protein-protein interactions and experimentally validated to delineate the important transcriptional regulators of  SESN3 . Our study revealed high confidence set of BMos (integrated with DNase I hypersensitivity sites) in the upstream regulatory regions of  SESN3  that could be bound by transcription factors from multiple families including  FOXOs ,  SMADs ,  SOXs ,  TCFs  and  HNF4A . TF-TF network analysis established hubs of interaction that include  SMAD3 ,  TCF3 ,  SMAD2 ,  HDAC2 ,  SOX2 ,  TAL1  and  TCF12  as well as the likely protein complexes formed between them. We show using ChIP-PCR as well as over-expression and knock out studies that  FOXO3  and  SOX2  transcriptionally regulate the expression of SESN3 gene. Our findings provide an important roadmap to further our understanding on the regulation of  SESN3 .

plos one

Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach