Neuronal Activity Suppresses NEUROD-Dependent Transcription and Genome Organization

Neuronal activity induces gene expression programs associated with plasticity in the brain, but it also transiently suppresses gene expression through poorly understood mechanisms. Here, we report that neuronal activity downregulates NEUROD-dependent gene expression in cerebellar granule neurons in adult mice. Using NEUROD1/2 double conditional knock-out mice of both sexes, we show that NEUROD binds and activates its target gene enhancers and establishes a three-dimensional genome architecture that facilitates transcription when neuronal activity is low. Moreover, NEUROD antagonizes activity-dependent gene expression programs, including those regulated by MEF2. However, when granule neurons are activated, NEUROD-dependent transcriptional and genome organizing functions are disrupted. Together, these findings reveal NEUROD as a key regulator of transcriptional programs associated with inactive neurons. Our study provides new insights into how neuronal activity reshapes gene transcription and genome architecture in the brain.