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A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology

BACKGROUND: Pancreatic adenocarcinoma (PAC) is one of the most intractable malignancies. In order to search for potential new therapeutic targets, we relied on computational methods aimed at identifying transcription factor binding sites (TFBSs) over-represented in the promoter regions of genes diff...

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Autores principales: Levkovitz, Liron, Yosef, Nir, Gershengorn, Marvin C., Ruppin, Eytan, Sharan, Roded, Oron, Yoram
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008686/
https://www.ncbi.nlm.nih.gov/pubmed/21203558
http://dx.doi.org/10.1371/journal.pone.0014423
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author Levkovitz, Liron
Yosef, Nir
Gershengorn, Marvin C.
Ruppin, Eytan
Sharan, Roded
Oron, Yoram
author_facet Levkovitz, Liron
Yosef, Nir
Gershengorn, Marvin C.
Ruppin, Eytan
Sharan, Roded
Oron, Yoram
author_sort Levkovitz, Liron
collection PubMed
description BACKGROUND: Pancreatic adenocarcinoma (PAC) is one of the most intractable malignancies. In order to search for potential new therapeutic targets, we relied on computational methods aimed at identifying transcription factor binding sites (TFBSs) over-represented in the promoter regions of genes differentially expressed in PAC. Though many computational methods have been implemented to accomplish this, none has gained overall acceptance or produced proven novel targets in PAC. To this end we have developed DEMON, a novel method for motif detection. METHODOLOGY: DEMON relies on a hidden Markov model to score the appearance of sequence motifs, taking into account all potential sites in a promoter of potentially varying binding affinities. We demonstrate DEMON's accuracy on simulated and real data sets. Applying DEMON to PAC-related data sets identifies the RUNX family as highly enriched in PAC-related genes. Using a novel experimental paradigm to distinguish between normal and PAC cells, we find that RUNX3 mRNA (but not RUNX1 or RUNX2 mRNAs) exhibits time-dependent increases in normal but not in PAC cells. These increases are accompanied by changes in mRNA levels of putative RUNX gene targets. CONCLUSIONS: The integrated application of DEMON and a novel differentiation system led to the identification of a single family member, RUNX3, which together with four of its putative targets showed a robust response to a differentiation stimulus in healthy cells, whereas this regulatory mechanism was absent in PAC cells, emphasizing RUNX3 as a promising target for further studies.
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spelling pubmed-30086862011-01-03 A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology Levkovitz, Liron Yosef, Nir Gershengorn, Marvin C. Ruppin, Eytan Sharan, Roded Oron, Yoram PLoS One Research Article BACKGROUND: Pancreatic adenocarcinoma (PAC) is one of the most intractable malignancies. In order to search for potential new therapeutic targets, we relied on computational methods aimed at identifying transcription factor binding sites (TFBSs) over-represented in the promoter regions of genes differentially expressed in PAC. Though many computational methods have been implemented to accomplish this, none has gained overall acceptance or produced proven novel targets in PAC. To this end we have developed DEMON, a novel method for motif detection. METHODOLOGY: DEMON relies on a hidden Markov model to score the appearance of sequence motifs, taking into account all potential sites in a promoter of potentially varying binding affinities. We demonstrate DEMON's accuracy on simulated and real data sets. Applying DEMON to PAC-related data sets identifies the RUNX family as highly enriched in PAC-related genes. Using a novel experimental paradigm to distinguish between normal and PAC cells, we find that RUNX3 mRNA (but not RUNX1 or RUNX2 mRNAs) exhibits time-dependent increases in normal but not in PAC cells. These increases are accompanied by changes in mRNA levels of putative RUNX gene targets. CONCLUSIONS: The integrated application of DEMON and a novel differentiation system led to the identification of a single family member, RUNX3, which together with four of its putative targets showed a robust response to a differentiation stimulus in healthy cells, whereas this regulatory mechanism was absent in PAC cells, emphasizing RUNX3 as a promising target for further studies. Public Library of Science 2010-12-22 /pmc/articles/PMC3008686/ /pubmed/21203558 http://dx.doi.org/10.1371/journal.pone.0014423 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Levkovitz, Liron
Yosef, Nir
Gershengorn, Marvin C.
Ruppin, Eytan
Sharan, Roded
Oron, Yoram
A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology
title A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology
title_full A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology
title_fullStr A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology
title_full_unstemmed A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology
title_short A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology
title_sort novel hmm-based method for detecting enriched transcription factor binding sites reveals runx3 as a potential target in pancreatic cancer biology
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008686/
https://www.ncbi.nlm.nih.gov/pubmed/21203558
http://dx.doi.org/10.1371/journal.pone.0014423
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