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KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-18 (2020), Digital.CSIC. Repositorio Institucional del CSIC, instname, Nature Communications
- Publication Year :
- 2020
- Publisher :
- Nature Portfolio, 2020.
-
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.<br />M.L. is recipient of a Santiago Grisolia fellowship given by the Generalitat Valenciana, J.M.C. is recipient of a fellowship from the Spanish Ministry of Education, Culture and Sport (MECD), J.F.-A. and C.M.N. are recipients of fellowships from the Spanish Ministry of Science and Innovation (MICINN). The ultrastructure research was supported by the Polish National Science Center Grant UMO-2014/15/N/NZ3/04468 and by the European Regional Development Fund POIG 01.01.02-00-008/08. J.P.L.-A. research is supported by Grants RYC-2015-18056 and RTI2018-102260-B-I00 from MICINN co-financed by ERDF. A.B. research is supported by Grants SAF2017-87928-R, PCIN-2015-192-C02-01, and SEV-2017-0723 from MICINN co-financed by ERDF, PROMETEO/2016/026 from the Generalitat Valenciana, and RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO). The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.
- Subjects :
- Male
0301 basic medicine
Epigenetic memory
Science
General Physics and Astronomy
Biology
Article
General Biochemistry, Genetics and Molecular Biology
Epigenome
03 medical and health sciences
0302 clinical medicine
Gene expression
Basic Helix-Loop-Helix Transcription Factors
Animals
p300-CBP Transcription Factors
Epigenetics in the nervous system
lcsh:Science
Enhancer
Transcription factor
Gene
Mice, Knockout
Neurons
Multidisciplinary
Transdifferentiation
Brain
Membrane Proteins
Acetylation
Promoter
General Chemistry
Lysine Acetyltransferases
Phosphoproteins
Cell biology
Enhancer Elements, Genetic
030104 developmental biology
Histone
Gene Expression Regulation
nervous system
biology.protein
Female
lcsh:Q
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....b61c7f5847ad00f33c479481b45962dd