Neuronal Activity-Driven 3D Chromatin Dynamics in Cortical Pyramidal Neurons Depend on SATB2 [RNA-Seq]

Here, we identify SATB2 as a central regulator of activity-dependent 3D chromatin dynamics in cortical pyramidal neurons. Using primary cultures from Satb2 conditional knockout mice, we combine Hi-C and chromatin accessibility mapping to capture rapid, epigenome reorganization upon near-physiological stimulation.

Within one hour, neurons exhibited enhanced chromatin compaction, loop strengthening, and formation of a novel activity-dependent (AD) compartment, enriched in SATB2 binding sites. AD compartment selectively mediates transient repression of metabolic and housekeeping genes, thereby prioritizing translation of long synaptic transcripts. SATB2 loss disrupted increased chromatin accessibility, long-range contacts, and AD compartmentalization, thus blunting both induction and repression of activity-regulated genes.