Dynamic Modulation of Neural Cell Identity Maintenance via Lysine Acetyltransferase Type 3 Protein Targeted Degradation

Abstract

Cell identity acquisition during central nervous system development leads to the establishment of cell-specific transcriptional programs. Once acquired, this identity must be actively maintained, among other molecular mechanisms, by the acetylation of cell-type-specific regulatory regions carried out by the lysine acetyltransferases type 3 (KAT3) proteins CBP and p300. Here, we characterize the rapid transcriptional and physiological consequences of KAT3 elimination in neuronal and glial lineages by means of a KAT3-specific PROTAC degrader, providing strong evidence for their central role as neural identity wardens. Importantly, the restoration of KAT3 proteins in glial cells after cell identity erasure resulted in the recovery of the original transcriptome and physiological functions, probing the dynamic nature of neural cell identities. These findings expand the role of CBP/p300 as identity wardens and challenge our perception of terminal cellular identities as static irrevocable states, opening new avenues for neural identity manipulation with biomedical purposes.