Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes. Inducing differentiation in HDAC1-deficient mouse ESCs resulted in early H3K9 deacetylation, Sox2 downregulation, and enhanced astrogliogenesis, whereas neuro-differentiation was almost suppressed. Neuro-differentiation of (wt) ESCs was characterized by H3K9 hyperacetylation that was associated with HDAC1 and HDAC3 depletion. Conversely, the hippocampi of schizophrenia-like animals showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3. The hippocampi of schizophrenia-like brains that were treated with the cannabinoid receptor-1 inverse antagonist AM251 expressed H3K9ac at the level observed in normal brains. Together, the results indicate that co-regulation of H3K9ac by HDAC1 and HDAC3 is important to both embryonic brain development and neuro-differentiation as well as the pathophysiology of a schizophrenia-like phenotype.

Behavioral and Social Neuroscience Group CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Chemical and Pharmaceutical Biology University of Groningen Groningen The Netherlands

Department of Biomedical and Biotechnological Sciences Section of Pharmacology School of Medicine University of Catania Catania Italy

Department of Radiology University of Groningen University Medical Center Groningen Groningen The Netherlands

Faculty of Medicine Department of Pharmacology Masaryk University Brno Czech Republic

Faculty of Medicine Institute for Drug Research Hebrew University of Jerusalem Jerusalem Israel

Faculty of Science Department of Experimental Biology Masaryk University Brno Czech Republic

Institute of Biophysics of the Czech Academy of Sciences v v i Brno Czech Republic

Institute of Scientific Instruments of the Czech Academy of Sciences v v i Brno Czech Republic

Max F Perutz Laboratories Vienna Biocenter Vienna Austria

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