Seizure enhances SUMOylation and zinc-finger transcriptional repression in neuronal nuclei

Abstract

A single episode of pilocarpine-induced status epilepticus can trigger the development of spontaneous recurrent seizures in a rodent model for epilepsy. The initial seizure-induced events in neuronal nuclei that lead to long-term changes in gene expression and cellular responses likely contribute toward epileptogenesis. Using a transgenic mouse model to specifically isolate excitatory neuronal nuclei, we profiled the seizure-induced nuclear proteome via tandem mass tag mass spectrometry and observed robust enrichment of nuclear proteins associated with the SUMOylation pathway. In parallel with nuclear proteome, we characterized nuclear gene expression by RNA sequencing which provided insights into seizure-driven transcriptional regulation and dynamics. Strikingly, we saw widespread downregulation of zinc-finger transcription factors, specifically proteins that harbor Krüppel-associated box (KRAB) domains. Our results provide a detailed snapshot of nuclear events induced by seizure activity and demonstrate a robust method for cell-type-specific nuclear profiling that can be applied to other cell types and models.