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

Michal Lipinski, Rafael Muñoz-Viana, Beatriz Blanco, Angel Marquez-Galera, Juan Medrano-Relinque, José M. Caramés, Andrzej A. Szczepankiewicz, Jordi Fernandez-Albert, Carmen M. Navarrón, Roman Olivares, Grzegorz M. Wilczyński, Santiago Canals, Jose P. Lopez-Atalaya and Angel Barco ()
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Michal Lipinski: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Rafael Muñoz-Viana: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Beatriz Blanco: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Angel Marquez-Galera: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Juan Medrano-Relinque: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
José M. Caramés: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Andrzej A. Szczepankiewicz: Polish Academy of Science
Jordi Fernandez-Albert: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Carmen M. Navarrón: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Roman Olivares: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Grzegorz M. Wilczyński: Polish Academy of Science
Santiago Canals: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Jose P. Lopez-Atalaya: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas
Angel Barco: Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16246-0

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