Abstract
The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear. Here, we show that the combined elimination of both proteins in forebrain excitatory neurons of adult mice resulted in a rapidly progressing neurological phenotype associated with severe ataxia, dendritic retraction and reduced electrical activity. At the molecular level, we observed the downregulation of neuronal genes, as well as decreased H3K27 acetylation and pro-neural transcription factor binding at the promoters and enhancers of canonical neuronal genes. The combined deletion of CBP and p300 in hippocampal neurons resulted in the rapid loss of neuronal molecular identity without de- or transdifferentiation. Restoring CBP expression or lysine acetylation rescued neuronal-specific transcription in cultured neurons. Together, these experiments show that KAT3 proteins maintain the excitatory neuron identity through the regulation of histone acetylation at cell type-specific promoter and enhancer regions.
Highlights
The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear
We used an inducible knockout system to demonstrate that KAT3 proteins are jointly required in excitatory neurons to preserve their postmitotic neuronal identity, thereby acting as fate-keepers
Supporting this view, a recent study showed that treatment with competitive inhibitors targeting the bromodomains of CBP and p300 enhanced the reprogramming of human fibroblasts into iPSCs, while KAT inhibition prevented iPSC formation[42]
Summary
The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear. To define KAT3-specific functions in the adult brain, we generate mice with inducible and restricted ablation of CBP and/ or p300 in forebrain principal neurons The characterization of these strains reveals that while both proteins are individually dispensable for the normal function of mature neurons, their combined ablation has devastating and rapid consequences: dendrites retract, synapses are lost, and electrical activity and neuron-specific gene programs established during development are shutdown. These phenotypes lead to severe neurological defects and premature death. Epigenomic screens and rescue experiments demonstrate that both KAT3 proteins are jointly essential for maintaining the identity of excitatory forebrain neurons (and likely other cell types) throughout life by preserving acetylation levels at cell type-specific genes and enhancers
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