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HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals

Večeřa, J., Bártová, E., Krejčí, J., Legartová, S., Komůrková, D., Rudá-Kučerová, J., Štark, T., Dražanová, E., Kašpárek, T., Šulcová, A., Dekker, F. J., Szymanski, W., Seiser, C., Weitzer, G., Mechoulam, R., Micale, V. & Kozubek, S. Jan-2018 In : Journal of Cellular Physiology. 233, 1, p. 530-548 19 p.

Research output: Scientific - peer-reviewArticle

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  • HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals

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DOI

  • Josef Večeřa
  • Eva Bártová
  • Jana Krejčí
  • Soňa Legartová
  • Denisa Komůrková
  • Jana Rudá-Kučerová
  • Tibor Štark
  • Eva Dražanová
  • Tomáš Kašpárek
  • Alexandra Šulcová
  • Frank J Dekker
  • Wiktor Szymanski
  • Christian Seiser
  • Georg Weitzer
  • Raphael Mechoulam
  • Vincenzo Micale
  • Stanislav Kozubek

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.

Original languageEnglish
Pages (from-to)530-548
Number of pages19
JournalJournal of Cellular Physiology
Volume233
Issue number1
StatePublished - Jan-2018

    Keywords

  • acetylome, H3K9 acetylation, HDACs, mouse neurogenesis, schizophrenia, CELL-ADHESION MOLECULE, HISTONE DEACETYLASE INHIBITORS, NEURONAL DIFFERENTIATION, STEM-CELLS, N-CAM, PREFRONTAL CORTEX, BIPOLAR DISORDER, VALPROIC ACID, RODENT MODEL, DOPAMINE D2

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