title: Stroke Induces Nuclear Shuttling of Histone Deacetylase 4.
abstract: OBJECTIVE
  Histone deacetylases (HDACs) 4 and 5 are abundantly expressed in the brain and have been implicated in the regulation of neurodegeneration. Under physiological conditions, HDACs 4 and 5 are expressed in the cytoplasm of brain cells where they cannot directly access chromatin. In response to external stimuli, they can shuttle to the nucleus and regulate gene expression. However, the effect of stroke on nuclear shuttling of HDACs 4 and 5 remains unknown.
  
  
  METHODS
  Using a rat model of middle cerebral artery occlusion, we examined the subcellular localization of HDACs 4 and 5 in the peri-infarct cortex during brain repair after stroke.
  
  
  RESULTS
  Stroke significantly increased nuclear HDAC4 immunoreactivity in neurons, but not in astrocytes or in oligodendrocytes, of the peri-infarct cortex at 2, 7, and 14 days after middle cerebral artery occlusion. Neurons with nuclear HDAC4 immunoreactivity distributed across all layers of the peri-infarct cortex and were Ctip2+ excitatory and parvalbumin+ inhibitory neurons. These neurons were not TUNEL or BrdU positive. Furthermore, nuclear HDAC4 immunoreactivity was positively and significantly correlated with increased dendritic, axonal, and myelin densities as determined by microtubule-associated protein 2, phosphorylated neurofilament heavy chain, and myelin basic protein, respectively. Unlike HDAC4, stroke did not alter nuclear localization of HDAC5.
  
  
  CONCLUSIONS
  Our data show that stroke induces nuclear shuttling of HDAC4 in neurons in the peri-infarct cortex, and that increased nuclear HDAC4 is strongly associated with neuronal remodeling but not with neuronal cell death, suggesting a role for nuclear HDAC4 in promoting neuronal recovery after ischemic injury.
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (H.K., A.S., M.C., C.R., Z.G.Z.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Haifa
authors.initials: H
authors.lastname: Kassis
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (H.K., A.S., M.C., C.R., Z.G.Z.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Amjad
authors.initials: A
authors.lastname: Shehadah
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (H.K., A.S., M.C., C.R., Z.G.Z.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (H.K., A.S., M.C., C.R., Z.G.Z.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (H.K., A.S., M.C., C.R., Z.G.Z.); and Department of Physics, Oakland University, Rochester, MI (M.C.). zhazh@neuro.hfh.edu.
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology* / Q000473:pathology; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
chemical_list: C559944:HDAC4 protein, rat; D006655:Histone Deacetylases
keywords: epigenenomics; stroke