Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/36987 http://dx.doi.org/10.1371/journal.pone.0079913 |
Resumo: | We previously described - studying transcriptional signatures of hippocampal CA3 explants - that febrile (FS) and afebrile (NFS) forms of refractory mesial temporal lobe epilepsy constitute two distinct genomic phenotypes. That network analysis was based on a limited number (hundreds) of differentially expressed genes (DE networks) among a large set of valid transcripts (close to two tens of thousands). Here we developed a methodology for complex network visualization (3D) and analysis that allows the categorization of network nodes according to distinct hierarchical levels of gene-gene connections (node degree) and of interconnection between node neighbors (concentric node degree). Hubs are highly connected nodes, VIPs have low node degree but connect only with hubs, and high-hubs have VIP status and high overall number of connections. Studying the whole set of CA3 valid transcripts we: i) obtained complete transcriptional networks (CO) for FS and NFS phenotypic groups; ii) examined how CO and de networks are related; iii) characterized genomic and molecular mechanisms underlying FS and NFS phenotypes, identifying potential novel targets for therapeutic interventions. We found that: i) de hubs and VIPs are evenly distributed inside the CO networks; ii) most de hubs and VIPs are related to synaptic transmission and neuronal excitability whereas most CO hubs, VIPs and high hubs are related to neuronal differentiation, homeostasis and neuroprotection, indicating compensatory mechanisms. Complex network visualization and analysis is a useful tool for systems biology approaches to multifactorial diseases. Network centrality observed for hubs, VIPs and high hubs of CO networks, is consistent with the network disease model, where a group of nodes whose perturbation leads to a disease phenotype occupies a central position in the network. Conceivably, the chance for exerting therapeutic effects through the modulation of particular genes will be higher if these genes are highly interconnected in transcriptional networks. |
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Bando, Silvia YumiSilva, Filipi NascimentoCosta, Luciano Da FontouraSilva, Alexandre Valotta da [UNIFESP]Pimentel-Silva, Luciana Ramalho [UNIFESP]Castro, Luiz H. M.Wen, Hung-TzuAmaro, EdsonMoreira-Filho, Carlos AlbertoUniversidade Federal de São Paulo (UNIFESP)Universidade de São Paulo (USP)2016-01-24T14:34:43Z2016-01-24T14:34:43Z2013-11-21Plos One. San Francisco: Public Library Science, v. 8, n. 11, 17 p., 2013.1932-6203http://repositorio.unifesp.br/handle/11600/36987http://dx.doi.org/10.1371/journal.pone.0079913WOS000327539800032.pdf10.1371/journal.pone.0079913WOS:000327539800032We previously described - studying transcriptional signatures of hippocampal CA3 explants - that febrile (FS) and afebrile (NFS) forms of refractory mesial temporal lobe epilepsy constitute two distinct genomic phenotypes. That network analysis was based on a limited number (hundreds) of differentially expressed genes (DE networks) among a large set of valid transcripts (close to two tens of thousands). Here we developed a methodology for complex network visualization (3D) and analysis that allows the categorization of network nodes according to distinct hierarchical levels of gene-gene connections (node degree) and of interconnection between node neighbors (concentric node degree). Hubs are highly connected nodes, VIPs have low node degree but connect only with hubs, and high-hubs have VIP status and high overall number of connections. Studying the whole set of CA3 valid transcripts we: i) obtained complete transcriptional networks (CO) for FS and NFS phenotypic groups; ii) examined how CO and de networks are related; iii) characterized genomic and molecular mechanisms underlying FS and NFS phenotypes, identifying potential novel targets for therapeutic interventions. We found that: i) de hubs and VIPs are evenly distributed inside the CO networks; ii) most de hubs and VIPs are related to synaptic transmission and neuronal excitability whereas most CO hubs, VIPs and high hubs are related to neuronal differentiation, homeostasis and neuroprotection, indicating compensatory mechanisms. Complex network visualization and analysis is a useful tool for systems biology approaches to multifactorial diseases. Network centrality observed for hubs, VIPs and high hubs of CO networks, is consistent with the network disease model, where a group of nodes whose perturbation leads to a disease phenotype occupies a central position in the network. Conceivably, the chance for exerting therapeutic effects through the modulation of particular genes will be higher if these genes are highly interconnected in transcriptional networks.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Fac Med, Dept Pediat, São Paulo, BrazilUniv São Paulo, Inst Fis Sao Carlos, Sao Carlos, SP, BrazilUniversidade Federal de São Paulo, Dept Biosci, Santos, SP, BrazilFMUSP, Hosp Clin, Clin Neurol Div, São Paulo, BrazilFMUSP, Hosp Clin, Epilepsy Surg Grp, São Paulo, BrazilUniv São Paulo, Fac Med, Dept Radiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, Santos, SP, BrazilFAPESP: 2009/53443-1FAPESP: 2005/56446-0FAPESP: 2005/00587-5FAPESP: 2011/50761-2CNPq: 305635/2009-3CNPq: 301303/06-1CNPq: 573583/2008-0Web of Science17engPublic Library SciencePlos OneComplex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsyinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000327539800032.pdfapplication/pdf5910265${dspace.ui.url}/bitstream/11600/36987/1/WOS000327539800032.pdf3bfbaf092208a44cfdd9c65acb31bca4MD51open accessTEXTWOS000327539800032.pdf.txtWOS000327539800032.pdf.txtExtracted texttext/plain91268${dspace.ui.url}/bitstream/11600/36987/6/WOS000327539800032.pdf.txtce9b9cd8190fa42c7b91cd9d0368cc0cMD56open accessTHUMBNAILWOS000327539800032.pdf.jpgWOS000327539800032.pdf.jpgIM Thumbnailimage/jpeg7913${dspace.ui.url}/bitstream/11600/36987/8/WOS000327539800032.pdf.jpgbb8dd6f0ad3fd983eaf4b01e368e9683MD58open access11600/369872023-06-05 19:11:31.75open accessoai:repositorio.unifesp.br:11600/36987Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-06-05T22:11:31Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy |
title |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy |
spellingShingle |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy Bando, Silvia Yumi |
title_short |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy |
title_full |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy |
title_fullStr |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy |
title_full_unstemmed |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy |
title_sort |
Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy |
author |
Bando, Silvia Yumi |
author_facet |
Bando, Silvia Yumi Silva, Filipi Nascimento Costa, Luciano Da Fontoura Silva, Alexandre Valotta da [UNIFESP] Pimentel-Silva, Luciana Ramalho [UNIFESP] Castro, Luiz H. M. Wen, Hung-Tzu Amaro, Edson Moreira-Filho, Carlos Alberto |
author_role |
author |
author2 |
Silva, Filipi Nascimento Costa, Luciano Da Fontoura Silva, Alexandre Valotta da [UNIFESP] Pimentel-Silva, Luciana Ramalho [UNIFESP] Castro, Luiz H. M. Wen, Hung-Tzu Amaro, Edson Moreira-Filho, Carlos Alberto |
author2_role |
author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Federal de São Paulo (UNIFESP) Universidade de São Paulo (USP) |
dc.contributor.author.fl_str_mv |
Bando, Silvia Yumi Silva, Filipi Nascimento Costa, Luciano Da Fontoura Silva, Alexandre Valotta da [UNIFESP] Pimentel-Silva, Luciana Ramalho [UNIFESP] Castro, Luiz H. M. Wen, Hung-Tzu Amaro, Edson Moreira-Filho, Carlos Alberto |
description |
We previously described - studying transcriptional signatures of hippocampal CA3 explants - that febrile (FS) and afebrile (NFS) forms of refractory mesial temporal lobe epilepsy constitute two distinct genomic phenotypes. That network analysis was based on a limited number (hundreds) of differentially expressed genes (DE networks) among a large set of valid transcripts (close to two tens of thousands). Here we developed a methodology for complex network visualization (3D) and analysis that allows the categorization of network nodes according to distinct hierarchical levels of gene-gene connections (node degree) and of interconnection between node neighbors (concentric node degree). Hubs are highly connected nodes, VIPs have low node degree but connect only with hubs, and high-hubs have VIP status and high overall number of connections. Studying the whole set of CA3 valid transcripts we: i) obtained complete transcriptional networks (CO) for FS and NFS phenotypic groups; ii) examined how CO and de networks are related; iii) characterized genomic and molecular mechanisms underlying FS and NFS phenotypes, identifying potential novel targets for therapeutic interventions. We found that: i) de hubs and VIPs are evenly distributed inside the CO networks; ii) most de hubs and VIPs are related to synaptic transmission and neuronal excitability whereas most CO hubs, VIPs and high hubs are related to neuronal differentiation, homeostasis and neuroprotection, indicating compensatory mechanisms. Complex network visualization and analysis is a useful tool for systems biology approaches to multifactorial diseases. Network centrality observed for hubs, VIPs and high hubs of CO networks, is consistent with the network disease model, where a group of nodes whose perturbation leads to a disease phenotype occupies a central position in the network. Conceivably, the chance for exerting therapeutic effects through the modulation of particular genes will be higher if these genes are highly interconnected in transcriptional networks. |
publishDate |
2013 |
dc.date.issued.fl_str_mv |
2013-11-21 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:34:43Z |
dc.date.available.fl_str_mv |
2016-01-24T14:34:43Z |
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info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
dc.identifier.citation.fl_str_mv |
Plos One. San Francisco: Public Library Science, v. 8, n. 11, 17 p., 2013. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/36987 http://dx.doi.org/10.1371/journal.pone.0079913 |
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1932-6203 |
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WOS000327539800032.pdf |
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10.1371/journal.pone.0079913 |
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Plos One. San Francisco: Public Library Science, v. 8, n. 11, 17 p., 2013. 1932-6203 WOS000327539800032.pdf 10.1371/journal.pone.0079913 WOS:000327539800032 |
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http://repositorio.unifesp.br/handle/11600/36987 http://dx.doi.org/10.1371/journal.pone.0079913 |
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