An NPAS4:NuA4 complex couples synaptic activity to DNA repair [ATAC-Seq]

Neuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is not known. Here we identify the first example of a neuronal-specific DNA repair mechanism via a new form of the NuA4/TIP60 chromatin modifier that assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex directly from the brain and demonstrate its function in eliciting activity-dependent changes to neuronal transcriptomes and neuronal circuitry. NPAS4:NuA4 binds at fragile regulatory regions that undergo neuronal activity-induced DNA double-strand breaks and recruits additional DNA repair machinery to stimulate the repair of these sites. Gene regulatory elements bound by the NPAS4:NuA4 complex are partially protected from age-dependent accumulation of somatic mutations. Impaired NPAS4:NuA4 signaling leads to a cascade of cellular defects including dysregulated transcriptional responses to activity, loss of control over neuronal inhibition, and genome instability, culminating in reduced longevity at the organismal level. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental disorders and autism. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation and whose disruption may contribute to developmental disorders, neurodegeneration and aging. Excitatory pyramidal neurons were isolated from the hippocampi of B6;129-Gt(ROSA)26Sor/J (Jackson labs Stock 021039) X B6.Cg-Tg(Camk2a-cre)T29-1Stl/J (Jackson labs Stock 005329) using the INTACT method. Mice were stimulated with glutamate agonist kainic acid and collected at either 0 or 2 hours post stimulation. Experiments were performed in triplicate.