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KAT3-dependent acetylation maintains neuronal identity in the adult mouse brain.

Lipinski M, Muñoz-Viana R, del Blanco B, Marquez-Galera A, Medrano-Relinque J, Carames JM, Szczepankiewicz A, Fernandez-Albert J, Navarrón CM, Olivares R, Wilczynski GM, Canals S, Lopez-Atalaya JP and Barco A.

Nat Comm. 11, 2588 (2020)
doi: 10.1038/s41467-020-16246-0
Published: 2020 May 22;

Link to the video: https://youtu.be/JEY8L5YF2Ps

Most of what we know about reprograming and the maintenance of cellular fate comes from studies in dividing cells, and we still do not know what makes a neuron to stay being a neuron for the whole life of the individual and. The study by Lipinski and colleagues identifies the lysine acetyltransferases CBP and p300 as key safeguards of cell fate and provides essential mechanistic insight on how neuronal identity is preserved throughout life. These two proteins are the only two members of the lysine acetyltransferases type 3 (KAT3) family. Although they are important and well-studied transcriptional co-activators, their specific functions in adult post-mitotic neurons remain unclear.

In the work just published in the journal Nature Communications, it is shown how by simultaneously eliminating CBP and p300 in the brains of adult mice, neurons lose their synaptic connections, as well as their ability to respond to electrical stimuli, in a few days. necessary for the functionality of the brain. This leads to a severe decrease in the ability to coordinate movements (ataxia) and loss of the basic reflexes of the animal. In parallel, at the molecular level there is a decrease in the regulation of neuronal genes.

It was previously known that CBP and p300 proteins actively participate in the process of cell differentiation, whereby each cell type acquires its specific morphology and functions, that is, its identity. The new study shows that precisely these two proteins are also responsible for maintaining this cellular identity throughout life. The simultaneous absence of CBP and p300 specifically prevents the expression of genes that confer identity to neurons. Therefore, the combined elimination of CBP and p300 in hippocampal neurons results in rapid loss of neuronal molecular identity without dedifferentiation or transdifferentiation of these cells. Although a loss of identity as dramatic as that observed when CBP and p300 are removed does not occur naturally, it is believed that some pathologies associated with aging may be due to an erosion of the epigenome and a partial loss of identity of some cell types, including neurons. CBP and p300 proteins are also linked to some types of cancer and to a rare disease, called Rubinstein-Taybi syndrome, associated with severe intellectual disability.

This multidisciplinary study required the collaboration of several labs with different expertise at the Neuroscience Institute, UMH-CSIC, in Alicante, with collaborators at the Nencki Institute in Warsaw.

This multidisciplinary study involves 14 researchers. The photography shows the main authors of the study in a meeting last December. From left to right: Rafael Muñoz-Viana, Angel Barco, Beatriz del Blanco y Michal Lipinski.

Lipinski et al. show that CBP and p300 (jointly referred to as KAT3) safeguard neuronal identity by regulating histone acetylation at promoter and enhancer regions of neuronal specific genes. The combined loss of these factors has severe effects on neuronal morphology, electric properties and gene expression. This loss of identity is represented in the image of dentate gyrus neurons with the progressive loss of resolution from left to right, in parallel with the reduction of KAT3 activity.

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