Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular mech...

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Autores principales:	Aleksej Zelezniak, Tune H Pers, Simão Soares, Mary Elizabeth Patti, Kiran Raosaheb Patil
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f98d720481d1419c8e5fc03d50c89ed7
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spelling	oai:doaj.org-article:f98d720481d1419c8e5fc03d50c89ed72021-11-25T05:42:34ZMetabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.1553-734X1553-735810.1371/journal.pcbi.1000729https://doaj.org/article/f98d720481d1419c8e5fc03d50c89ed72010-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20369014/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites--metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment of binding sites in the promoter regions of these genes. In addition to metabolites from TCA cycle, oxidative phosphorylation, and lipid metabolism (known to be associated with T2DM), we identified several reporter metabolites representing novel biomarker candidates. For example, the highly connected metabolites NAD+/NADH and ATP/ADP were also identified as reporter metabolites that are potentially contributing to the widespread gene expression changes observed in T2DM. An algorithm based on the analysis of the promoter regions of the genes associated with reporter metabolites revealed a transcription factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic and regulatory nodes potentially involved in the pathogenesis of T2DM.Aleksej ZelezniakTune H PersSimão SoaresMary Elizabeth PattiKiran Raosaheb PatilPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 6, Iss 4, p e1000729 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Aleksej Zelezniak Tune H Pers Simão Soares Mary Elizabeth Patti Kiran Raosaheb Patil Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
description	Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites--metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment of binding sites in the promoter regions of these genes. In addition to metabolites from TCA cycle, oxidative phosphorylation, and lipid metabolism (known to be associated with T2DM), we identified several reporter metabolites representing novel biomarker candidates. For example, the highly connected metabolites NAD+/NADH and ATP/ADP were also identified as reporter metabolites that are potentially contributing to the widespread gene expression changes observed in T2DM. An algorithm based on the analysis of the promoter regions of the genes associated with reporter metabolites revealed a transcription factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic and regulatory nodes potentially involved in the pathogenesis of T2DM.
format	article
author	Aleksej Zelezniak Tune H Pers Simão Soares Mary Elizabeth Patti Kiran Raosaheb Patil
author_facet	Aleksej Zelezniak Tune H Pers Simão Soares Mary Elizabeth Patti Kiran Raosaheb Patil
author_sort	Aleksej Zelezniak
title	Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
title_short	Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
title_full	Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
title_fullStr	Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
title_full_unstemmed	Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
title_sort	metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/f98d720481d1419c8e5fc03d50c89ed7
work_keys_str_mv	AT aleksejzelezniak metabolicnetworktopologyrevealstranscriptionalregulatorysignaturesoftype2diabetes AT tunehpers metabolicnetworktopologyrevealstranscriptionalregulatorysignaturesoftype2diabetes AT simaosoares metabolicnetworktopologyrevealstranscriptionalregulatorysignaturesoftype2diabetes AT maryelizabethpatti metabolicnetworktopologyrevealstranscriptionalregulatorysignaturesoftype2diabetes AT kiranraosahebpatil metabolicnetworktopologyrevealstranscriptionalregulatorysignaturesoftype2diabetes
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Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.

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