Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy
Autor(a) principal: | |
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Data de Publicação: | 2011 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/34146 http://dx.doi.org/10.1371/journal.pone.0026268 |
Resumo: | Background: Prolonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). in order to investigate IPI influence on the transcriptional phenotype underlying RMTLE we comparatively analyzed the transcriptomic signatures of CA3 explants surgically obtained from RMTLE patients with (FS) or without (NFS) febrile seizure history. Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations.Methodology/Principal Findings: DNA microarray analysis revealed that CA3 global gene expression differed significantly between FS and NFS subgroups. An integrative functional genomics methodology was used for characterizing the relations between GO biological processes themes and constructing transcriptional interaction networks defining the FS and NFS transcriptomic signatures and its major gene-gene links (hubs). Co-expression network analysis showed that: i) CA3 transcriptomic profiles differ according to the IPI; ii) FS distinctive hubs are mostly linked to glutamatergic signalization while NFS hubs predominantly involve GABAergic pathways and neurotransmission modulation. Both networks have relevant hubs related to nervous system development, what is consistent with cell genesis activity in the hippocampus of RMTLE patients. Moreover, two candidate genes for therapeutic targeting came out from this analysis: SSTR1, a relevant common hub in febrile and afebrile transcriptomes, and CHRM3, due to its putative role in epilepsy susceptibility development. MRI texture analysis allowed an overall accuracy of 90% for pixels correctly classified as belonging to FS or NFS groups. Histological examination revealed that granule cell loss was significantly higher in FS hippocampi.Conclusions/Significance: CA3 transcriptional signatures and dentate gyrus morphology fairly correlate with IPI in RMTLE, indicating that FS-RMTLE represents a distinct phenotype. These findings may shed light on the molecular mechanisms underlying refractory epilepsy phenotypes and contribute to the discovery of novel specific drug targets for therapeutic interventions. |
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Bando, Silvia Y.Alegro, Maryana C.Amaro, EdsonSilva, Alexandre V. [UNIFESP]Castro, Luiz H. M.Wen, Hung-TzuLima, Leandro de A.Brentani, HelenaMoreira-Filho, Carlos AlbertoUniversidade Federal de São Paulo (UNIFESP)Universidade de São Paulo (USP)Hosp Canc AC Camargo2016-01-24T14:17:19Z2016-01-24T14:17:19Z2011-10-14Plos One. San Francisco: Public Library Science, v. 6, n. 10, 12 p., 2011.1932-6203http://repositorio.unifesp.br/handle/11600/34146http://dx.doi.org/10.1371/journal.pone.0026268WOS000295981600044.pdf10.1371/journal.pone.0026268WOS:000295981600044Background: Prolonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). in order to investigate IPI influence on the transcriptional phenotype underlying RMTLE we comparatively analyzed the transcriptomic signatures of CA3 explants surgically obtained from RMTLE patients with (FS) or without (NFS) febrile seizure history. Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations.Methodology/Principal Findings: DNA microarray analysis revealed that CA3 global gene expression differed significantly between FS and NFS subgroups. An integrative functional genomics methodology was used for characterizing the relations between GO biological processes themes and constructing transcriptional interaction networks defining the FS and NFS transcriptomic signatures and its major gene-gene links (hubs). Co-expression network analysis showed that: i) CA3 transcriptomic profiles differ according to the IPI; ii) FS distinctive hubs are mostly linked to glutamatergic signalization while NFS hubs predominantly involve GABAergic pathways and neurotransmission modulation. Both networks have relevant hubs related to nervous system development, what is consistent with cell genesis activity in the hippocampus of RMTLE patients. Moreover, two candidate genes for therapeutic targeting came out from this analysis: SSTR1, a relevant common hub in febrile and afebrile transcriptomes, and CHRM3, due to its putative role in epilepsy susceptibility development. MRI texture analysis allowed an overall accuracy of 90% for pixels correctly classified as belonging to FS or NFS groups. Histological examination revealed that granule cell loss was significantly higher in FS hippocampi.Conclusions/Significance: CA3 transcriptional signatures and dentate gyrus morphology fairly correlate with IPI in RMTLE, indicating that FS-RMTLE represents a distinct phenotype. These findings may shed light on the molecular mechanisms underlying refractory epilepsy phenotypes and contribute to the discovery of novel specific drug targets for therapeutic interventions.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, Escola Politecn, Integrated Syst Lab, São Paulo, BrazilUniv São Paulo, Fac Med, Dept Radiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, São Paulo, BrazilUniv São Paulo, Fac Med, Hosp Clin, Clin Neurol Div, São Paulo, BrazilUniv São Paulo, Fac Med, Hosp Clin, Epilepsy Surg Grp, São Paulo, BrazilHosp Canc AC Camargo, Biotechnol Lab, São Paulo, BrazilUniv São Paulo, Fac Med, Dept Psychiat, Inst Nacl Psiquiatria Desenvolvimento, São Paulo, BrazilUniv São Paulo, Fac Med, Lab Invest Med 23, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, São Paulo, BrazilFAPESP: 2005/56.446-0CNPq: 475051/2009-2Web of Science12engPublic Library SciencePlos OneHippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial 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:UNIFESPORIGINALWOS000295981600044.pdfapplication/pdf909627${dspace.ui.url}/bitstream/11600/34146/1/WOS000295981600044.pdf510184421e85c35a61d0f468013e0f80MD51open accessTEXTWOS000295981600044.pdf.txtWOS000295981600044.pdf.txtExtracted texttext/plain64024${dspace.ui.url}/bitstream/11600/34146/2/WOS000295981600044.pdf.txt5924e05f61b29f41528352df94d62f97MD52open access11600/341462022-09-27 11:31:10.366open accessoai:repositorio.unifesp.br:11600/34146Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652022-09-27T14:31:10Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy |
title |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy |
spellingShingle |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy Bando, Silvia Y. |
title_short |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy |
title_full |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy |
title_fullStr |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy |
title_full_unstemmed |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy |
title_sort |
Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy |
author |
Bando, Silvia Y. |
author_facet |
Bando, Silvia Y. Alegro, Maryana C. Amaro, Edson Silva, Alexandre V. [UNIFESP] Castro, Luiz H. M. Wen, Hung-Tzu Lima, Leandro de A. Brentani, Helena Moreira-Filho, Carlos Alberto |
author_role |
author |
author2 |
Alegro, Maryana C. Amaro, Edson Silva, Alexandre V. [UNIFESP] Castro, Luiz H. M. Wen, Hung-Tzu Lima, Leandro de A. Brentani, Helena 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) Hosp Canc AC Camargo |
dc.contributor.author.fl_str_mv |
Bando, Silvia Y. Alegro, Maryana C. Amaro, Edson Silva, Alexandre V. [UNIFESP] Castro, Luiz H. M. Wen, Hung-Tzu Lima, Leandro de A. Brentani, Helena Moreira-Filho, Carlos Alberto |
description |
Background: Prolonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). in order to investigate IPI influence on the transcriptional phenotype underlying RMTLE we comparatively analyzed the transcriptomic signatures of CA3 explants surgically obtained from RMTLE patients with (FS) or without (NFS) febrile seizure history. Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations.Methodology/Principal Findings: DNA microarray analysis revealed that CA3 global gene expression differed significantly between FS and NFS subgroups. An integrative functional genomics methodology was used for characterizing the relations between GO biological processes themes and constructing transcriptional interaction networks defining the FS and NFS transcriptomic signatures and its major gene-gene links (hubs). Co-expression network analysis showed that: i) CA3 transcriptomic profiles differ according to the IPI; ii) FS distinctive hubs are mostly linked to glutamatergic signalization while NFS hubs predominantly involve GABAergic pathways and neurotransmission modulation. Both networks have relevant hubs related to nervous system development, what is consistent with cell genesis activity in the hippocampus of RMTLE patients. Moreover, two candidate genes for therapeutic targeting came out from this analysis: SSTR1, a relevant common hub in febrile and afebrile transcriptomes, and CHRM3, due to its putative role in epilepsy susceptibility development. MRI texture analysis allowed an overall accuracy of 90% for pixels correctly classified as belonging to FS or NFS groups. Histological examination revealed that granule cell loss was significantly higher in FS hippocampi.Conclusions/Significance: CA3 transcriptional signatures and dentate gyrus morphology fairly correlate with IPI in RMTLE, indicating that FS-RMTLE represents a distinct phenotype. These findings may shed light on the molecular mechanisms underlying refractory epilepsy phenotypes and contribute to the discovery of novel specific drug targets for therapeutic interventions. |
publishDate |
2011 |
dc.date.issued.fl_str_mv |
2011-10-14 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:17:19Z |
dc.date.available.fl_str_mv |
2016-01-24T14:17:19Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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Plos One. San Francisco: Public Library Science, v. 6, n. 10, 12 p., 2011. |
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http://repositorio.unifesp.br/handle/11600/34146 http://dx.doi.org/10.1371/journal.pone.0026268 |
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1932-6203 |
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WOS000295981600044.pdf |
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10.1371/journal.pone.0026268 |
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Plos One. San Francisco: Public Library Science, v. 6, n. 10, 12 p., 2011. 1932-6203 WOS000295981600044.pdf 10.1371/journal.pone.0026268 WOS:000295981600044 |
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http://repositorio.unifesp.br/handle/11600/34146 http://dx.doi.org/10.1371/journal.pone.0026268 |
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