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

Activity-dependent transcription plays a crucial role in neuronal plasticity, according to a recent study. The researchers discovered that neuronal activation leads to a widespread movement of the CBP and p300 proteins within hippocampal neurons. Upon stimulation, the KAT3 cofactors switch from super-enhancers that support neuronal identity to enhancers that are linked to genes regulated by activity.

This relocation is associated with temporary alterations in H3K27ac, chromatin accessibility, and the three-dimensional organization of the genome. The study reveals that different transcription factor families are responsible for controlling the transfer of KAT3. Proneural bHLH factors, such as NeuroD2, help maintain the cofactor's presence at identity-associated regulatory elements, while AP-1 binds to new sites at plasticity-associated locations.

This dynamic shift in KAT3 distribution alters enhancer landscapes and chromatin interactions, allowing for the efficient activation of plasticity genes while temporarily suppressing neuronal identity programs. Interestingly, the researchers found that increasing levels of FOS can replicate the repression of neuronal identity genes that occurs during stimulation.

Overall, the findings of this study demonstrate a reversible competition between transcriptional networks that regulate neuronal identity and plasticity, and identify KAT3 redistribution as a critical mechanism that links neuronal activity to extensive chromatin remodeling.