title: HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals.
abstract: 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.
authors.affiliation: Faculty of Science, Department of Experimental Biology, Masaryk University, Brno, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Večeřa
authors.affiliation: Institute of Biophysics of the Czech Academy of Sciences, v.v.i., Brno, Czech Republic.
authors.forename: Eva
authors.identifier: http://orcid.org/0000-0003-1299-0470
authors.initials: E
authors.lastname: Bártová
authors.affiliation: Institute of Biophysics of the Czech Academy of Sciences, v.v.i., Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Krejčí
authors.affiliation: Institute of Biophysics of the Czech Academy of Sciences, v.v.i., Brno, Czech Republic.
authors.forename: Soňa
authors.initials: S
authors.lastname: Legartová
authors.affiliation: Institute of Biophysics of the Czech Academy of Sciences, v.v.i., Brno, Czech Republic.
authors.forename: Denisa
authors.initials: D
authors.lastname: Komůrková
authors.affiliation: Faculty of Medicine, Department of Pharmacology, Masaryk University, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Rudá-Kučerová
authors.affiliation: Faculty of Medicine, Department of Pharmacology, Masaryk University, Brno, Czech Republic.
authors.forename: Tibor
authors.initials: T
authors.lastname: Štark
authors.affiliation: Faculty of Medicine, Department of Pharmacology, Masaryk University, Brno, Czech Republic.|Institute of Scientific Instruments of the Czech Academy of Sciences, v.v.i., Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Dražanová
authors.affiliation: Behavioral and Social Neuroscience Group, CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Kašpárek
authors.affiliation: Behavioral and Social Neuroscience Group, CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Šulcová
authors.affiliation: Chemical and Pharmaceutical Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
authors.affiliation: Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Wiktor
authors.initials: W
authors.lastname: Szymanski
authors.affiliation: Max F. Perutz Laboratories, Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Seiser
authors.affiliation: Max F. Perutz Laboratories, Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Weitzer
authors.affiliation: Faculty of Medicine, Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
authors.affiliation: Behavioral and Social Neuroscience Group, CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic.|Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Catania, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Micale
authors.affiliation: Faculty of Science, Department of Experimental Biology, Masaryk University, Brno, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kozubek
mesh_terms: D000107:Acetylation; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000201:enzymology* / Q000473:pathology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008746:Methylazoxymethanol Acetate; D008810:Mice, Inbred C57BL; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D000099186:Histone Deacetylase 3
chemical_list: D014150:Antipsychotic Agents; D063387:Cannabinoid Receptor Antagonists; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D008746:Methylazoxymethanol Acetate; D019006:Neural Cell Adhesion Molecules; D043884:Receptor, Cannabinoid, CB1; D055748:SOXB1 Transcription Factors; D000099186:Histone Deacetylase 3; C543264:Cnr1 protein, rat; C527783:Sox2 protein, mouse; C484389:Hdac1 protein, mouse; C515890:Hdac1 protein, rat
keywords: H3K9 acetylation; HDACs; acetylome; mouse neurogenesis; schizophrenia