Complex Network Analysis of CA3 Transcriptome Reveals Pathogenic and Compensatory Pathways in Refractory Temporal Lobe Epilepsy

Author(s)

Bando, Silvia Yumi ^[1] ; Silva, Filipi Nascimento ^[2] ; Costa, Luciano Da Fontoura ^[2] ; Silva, Alexandre V. ^[3] ; Pimentel-Silva, Luciana R. ^[3] ; Castro, Luiz H. M. ^[4] ; Wen, Hung-Tzu ^[5] ; Amaro, Jr., Edson ^[6] ; Moreira-Filho, Carlos Alberto ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Dept Pediat, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Fis Sao Carlos, Sao Carlos, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Biosci, Santos, SP - Brazil

^[4] FMUSP, Hosp Clin, Clin Neurol Div, Sao Paulo - Brazil

^[5] FMUSP, Hosp Clin, Epilepsy Surg Grp, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Fac Med, Dept Radiol, Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS One; v. 8, n. 11 NOV 21 2013.
• Web of Science Citations: 12

Abstract

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. (AU)

• FAPESP's process: 05/56446-0 - High resolutions structural MRI and receptor imaging studies in refractory temporal lobe epilepsy: in vivo and ex vivo analyses
• Grantee: Edson Amaro Junior
• Support type: Inter-institutional Cooperation in Support of Brain Research (CINAPCE) - Thematic Grants
• FAPESP's process: 11/50761-2 - Models and methods of e-Science for life and agricultural sciences
• Grantee: Roberto Marcondes Cesar Junior
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 05/00587-5 - Mesh (graph) modeling and techniques of pattern recognition: structure, dynamics and applications
• Grantee: Roberto Marcondes Cesar Junior
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 09/53443-1 - Neuroimmunology, functional genomics and neuroimaging: an integrated approach for studying physiopathology and treatment in refractory epilepsy
• Grantee: Carlos Alberto Moreira Filho
• Support type: Research Projects - Thematic Grants