KAT3 Shuttling Between Neuronal Identity and Activity-Dependent Plasticity Programs Drives Large-Scale Chromatin Remodeling

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ABSTRACT Activity-dependent transcription is a central feature of neuronal plasticity. Here, we show that neuronal activation triggers genome-wide redistribution of CBP and p300 in hippocampal neurons. Upon stimulation, KAT3 cofactors relocate from super-enhancers supporting neuronal identity to enhancers associated with activity-regulated genes, accompanied by transient changes in H3K27ac, chromatin accessibility, and three-dimensional genome architecture. Mechanistically, distinct TF families control KAT3 shuttling: proneural bHLH factors such as NeuroD2 maintain cofactor occupancy at identity-associated regulatory elements, whereas AP-1 binds de novo at plasticity-associated loci. This dynamic redistribution reshapes enhancer landscapes and chromatin interactions, enabling robust activation of plasticity genes while transiently attenuating neuronal identity programs. Remarkably, FOS overexpression is sufficient to reproduce the repression of neuronal identity genes observed during stimulation. Together, our findings reveal a reversible competition between transcriptional networks governing neuronal identity and plasticity and identify KAT3 redistribution as a key mechanism coupling neuronal activity to large-scale chromatin remodeling.

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