Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unknown, which hinders the discovery of effective anti-epileptogenic drugs. In this study, we built a systems-level analytic framework which integrates gene meta-signatures, gene coexpression network and cellular regulatory network to unveil the evolution landscape of epileptogenic process and to identify key regulators that govern the transition between different epileptogenesis stages. The time-specific hippocampal transcriptomic profiles from five independent rodent TLE models were grouped into acute, latent and chronic stages of epileptogenesis, and were utilized for generating stage-specific gene expression signatures. 13 cell-type specific functional modules were identified from the epilepsy-context coexpression network, and five of them were significantly associated with the entire epileptogenic process. By inferring the differential protein activity of gene regulators in each stage, 265 key regulators underlying epileptogenesis were obtained. Among them, 122 regulators were demonstrated being associated with high seizure frequency and/or hippocampal sclerosis in human TLE patients. Importantly, we discovered four new gene regulators (ANXA5, FAM107A, SEPT2 and SPARC) whose upregulation may drive the process of epileptogenesis and further lead to chronic recurrent seizures or hippocampal sclerosis. Our findings provide a landscape of the gene network dynamics underlying epileptogenesis and uncovered candidate regulators that may serve as potential targets for future anti-epileptogenic therapy development.