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

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 phyloge...

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Autores principales: Srivastava, Rajneesh, Zhang, Yang, Xiong, Xiwen, Zhang, Xiaoning, Pan, Xiaoyan, Dong, X. Charlie, Liangpunsakul, Suthat, Janga, Sarath Chandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965051/
https://www.ncbi.nlm.nih.gov/pubmed/27466818
http://dx.doi.org/10.1371/journal.pone.0160228
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author Srivastava, Rajneesh
Zhang, Yang
Xiong, Xiwen
Zhang, Xiaoning
Pan, Xiaoyan
Dong, X. Charlie
Liangpunsakul, Suthat
Janga, Sarath Chandra
author_facet Srivastava, Rajneesh
Zhang, Yang
Xiong, Xiwen
Zhang, Xiaoning
Pan, Xiaoyan
Dong, X. Charlie
Liangpunsakul, Suthat
Janga, Sarath Chandra
author_sort Srivastava, Rajneesh
collection PubMed
description 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.
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spelling pubmed-49650512016-08-18 Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach Srivastava, Rajneesh Zhang, Yang Xiong, Xiwen Zhang, Xiaoning Pan, Xiaoyan Dong, X. Charlie Liangpunsakul, Suthat Janga, Sarath Chandra PLoS One Research Article 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. Public Library of Science 2016-07-28 /pmc/articles/PMC4965051/ /pubmed/27466818 http://dx.doi.org/10.1371/journal.pone.0160228 Text en © 2016 Srivastava et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Srivastava, Rajneesh
Zhang, Yang
Xiong, Xiwen
Zhang, Xiaoning
Pan, Xiaoyan
Dong, X. Charlie
Liangpunsakul, Suthat
Janga, Sarath Chandra
Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach
title Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach
title_full Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach
title_fullStr Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach
title_full_unstemmed Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach
title_short Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach
title_sort prediction and validation of transcription factors modulating the expression of sestrin3 gene using an integrated computational and experimental approach
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965051/
https://www.ncbi.nlm.nih.gov/pubmed/27466818
http://dx.doi.org/10.1371/journal.pone.0160228
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