KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain

The acquisition of neuronal identity requires the coordinated action of transcription factors and chromatin-modifying enzymes. However, little is known about the mechanisms that are responsible for maintaining neuronal identity throughout life. The paralogous lysine acetyltransferases CBP and p300 are both essential during development, but their specific function in postmitotic neurons remains unclear. Here, we show that when both KATs are simultaneously knocked out in excitatory neurons of the mouse adult brain, the mice express a rapidly progressing neurological phenotype. This phenotype is associated with a loss of physiological, morphological and transcriptional features defining excitatory neuron identity. This correlates with a dramatic loss of H3K27 acetylation and occupancy by pro-neural transcription factors at neuron-specific genes and enhancers. Restoring CBP expression or lysine acetylation restitutes neuronal-specific gene expression. These experiments demonstrate that CBP and p300 are jointly necessary for maintaining neuronal identity and function by preserving correct chromatin acetylation levels in the adult brain. ChIP-seq for CBP and p300 in the hippocampus of inducible and forebrain excitatory neuron-restricted knockouts for Crebbp (CBP-ifKO), Ep300 (p300-ifKO or both proteins (dKAT3-ifKO), and their controls. mRNA-seq in the hippocampus of dKAT3-ifKOs and controls. ATAC-seq in forebrain excitatory neurons of dKAT3-ifKOs and controls. ChIP-seq for H3K27ac and H3K9,14ac in the hippocampus of dKAT3-ifKOs and controls. Single nucleus (sn)RNA-seq in the hippocampus of dKAT3-ifKOs and controls.