Nup153 regulates neural activity-dependent gene programs through HDAC1-mediated repression

Neuronal activity-dependent gene regulation is a fundamental mechanism to the development of neural networks and neuronal plasticity. Balancing the induction of activity-dependent gene programs and the repression of these programs are equally important. Here, we identify nucleoporin-dependent regulation of neuronal responsiveness in which Nup153 represses activity-regulated genes (ARGs) in the basal state. By characterizing the landscape of chromatin accessibility and the status of histone modifications in basal state neurons, we show that Nup153 directly regulates ARGs and chromatin organization in an activity-dependent and -independent manner. Mechanistically, Nup153 recruits HDAC1 to repress target genes and regulates histone acetylation. We propose that Nup153 acts as a structural platform to recruit epigenetic repressor mac to maintain activity-dependent programs in the poised state, thus maintaining neuronal responsiveness as a gatekeeper.