Nup153 regulates neuronal responsiveness through HDAC1-mediated epigenetic modulation [DamID-seq]

Neural activity-dependent gene regulation is central to the development of neural networks and neuronal plasticity. Induction of activity-dependent gene programs is equally important as repression of these programs, and both need to be balanced carefully. However, little is known about how repressive mechanisms modulate neuronal responsiveness across the genome before stimulation. Here, we identify nucleoporin-dependent regulation of neuronal responsiveness in which Nup153 represses neuronal genes including activity-regulated genes (ARGs) in the basal state. By characterizing the genome-wide landscape of chromatin accessibility, histone modifications and Nup153 chromatin binding, we show that Nup153 directly influences their target genes and associated chromatin states through both basal activity-dependent and -independent mechanisms. Mechanistically, Nup153 recruits HDAC1 to regulate histone acetylation and repress target chromatin regions. We propose that Nup153 acts as a structural platform to recruit epigenetic repressor to maintain activity-dependent programs in the poised state, thus maintaining neuronal responsiveness as a gatekeeper.