Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy

PLoS One. 2013 Nov 21;8(11):e79913. doi: 10.1371/journal.pone.0079913. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CA3 Region, Hippocampal / metabolism*
  • CA3 Region, Hippocampal / pathology
  • CA3 Region, Hippocampal / physiopathology
  • Epilepsy, Temporal Lobe / metabolism*
  • Epilepsy, Temporal Lobe / pathology
  • Epilepsy, Temporal Lobe / physiopathology
  • Gene Expression Profiling
  • Humans
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription, Genetic
  • Transcriptome*

Substances

  • RNA, Messenger

Grants and funding

This work was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) research grants 2009/53443-1 and 2005/56446-0 and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant 305635/2009-3 to CAM-F. L da FC was funded by FAPESP grants 2005/00587- 5 and 2011/50761-2 and CNPq grants 301303/06-1 and 573583/2008-0). CAM-F and L da FC are funded by FAPESP-MCT/CNPq/PRONEX grant 2011/50761-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.