PROTAC-MEDIATED TRANSIENT KAT3 DEGRADATION REVERSIBLY DISRUPTS CELL IDENTITY AND FUNCTION IN NEURAL CELLS

During development, neural progenitors differentiate through chromatin remodeling processes mediated by transcription factors and chromatin-modifying enzymes. Among these, the KAT3 lysine acetyltransferases CBP and p300 appear to play a critical role in this process, as proven by the dramatic collapse in cellular identity caused by their combined elimination in excitatory neurons of the adult mouse brain. Whether similar epigenetic dynamics operate in other neural cell lineages and prolonged loss of KAT3 activity induces chromatin disruptions that can lead to irreversible epigenetic states remains unknown. To address this, we used neuronal and mixed glial primary cultures derived from embryonic and postnatal mouse brain, respectively, and acutely depleted CBP and p300 using the KAT3-specific Proteolysis Targeting Chimera (PROTAC) degrader dCBP-1. KAT3 elimination induced widespread transcriptomic alterations, characterized by the downregulation of lineage-specific cell identity genes and accompanied by functional impairments in phagocytosis and cell migration in glial cells. Remarkably, following dCBP-1 washout in glial cells, CBP and p300 protein levels recovered over the course of a week, accompanied by an almost complete restoration of transcriptomic profiles and glial physiological functions. These findings suggest a more general role of KAT3 proteins than previously anticipated as neural identity keepers and reveal a substantial capacity for epigenetic identity restatement after transient epigenetic perturbations, highlighting the dynamic nature of chromatin-based control of epigenetic neural cell identity. Our findings open new avenues for the pharmacological targeting of KAT3 proteins to reversibly modulate cell-identity, with potential biomedical applications in cell reprogramming based strategies.