Neuronal activity triggers precise transcriptional programs that underlie synaptic plasticity and higher cognitive processes. These programs require rapid and coordinated reorganization of the three-dimensional (3D) genome, yet the molecular mechanisms that couple chromatin architecture to gene regulation remain unclear.
Using functional genomics assays in primary cortical neurons, we observed that within one hour of activation, neurons undergo accessibility changes, chromatin compaction and loop strengthening. We also observed the emergence of a distinct activity-dependent (AD) chromatin compartment enriched for binding sites of the genome organizer SATB2. This dynamic compartment orchestrates the selective repression of short metabolic and housekeeping genes while facilitating the translation and activation of long, synaptic function-related transcripts, ensuring temporal coordination of neuronal responses.
In neurons lacking SATB2, these dynamic structural transitions were profoundly disrupted, including reduced chromatin accessibility and failure to form the AD compartment. Consequently, both the induction of activity-regulated genes and the repression of constitutive programs were impaired, demonstrating that SATB2 is required for the full spectrum of neuronal transcriptional responses.
Together, these findings reveal that SATB2-mediated 3D genome architecture is essential for activity-dependent gene regulation in cortical neurons. By integrating higher-order chromatin organization with transcriptional control, SATB2 coordinates the balance between activation and repression necessary for neuronal plasticity. This work establishes a framework linking dynamic genome topology to gene expression, providing a mechanistic insight into how spatial genome organization contributs to the adaptability of cortical circuits and cognitive function.