KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain
Por:
Lipinski, M, Munoz-Viana, R, del Blanco, B, Marquez-Galera, A, Medrano-Relinque, J, Carames, J, Szczepankiewicz, A, Fernandez-Albert, J, Navarron, C, Olivares, R, Wilczynski, G, Canals, S, Lopez-Atalaya, J and Barco, A
Publicada:
22 may 2020
Resumen:
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. Neuronal identity maintenance is highly regulated. Here, the authors showed that CBP and p300 safeguard neuronal identity through histone acetylation at promoters and enhancers of neuronal specific genes. The loss of both CBP and p300 impairs gene expression, circuit activity, and behavior in mice.
Filiaciones:
Lipinski, M:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Munoz-Viana, R:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
del Blanco, B:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Marquez-Galera, A:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Medrano-Relinque, J:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Carames, J:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Szczepankiewicz, A:
Polish Acad Sci, Nencki Inst Expt Biol, 3 Pasteur St, PL-02093 Warsaw, Poland
Fernandez-Albert, J:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Navarron, C:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Olivares, R:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Wilczynski, G:
Polish Acad Sci, Nencki Inst Expt Biol, 3 Pasteur St, PL-02093 Warsaw, Poland
:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
Lopez-Atalaya, J:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Ave Santiago Ramon & Cajal S-N, Alicante 03550, Spain
gold, Green Published, Green Submitted
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