title: Nuclear translocation of histone deacetylase 4 induces neuronal death in stroke.
abstract: Mounting evidence suggests that epigenetic modifications play critical roles in the survival/death of stressed neurons. Chief among these modifications is the deacetylation of histones within the chromatin by histone deacetylases (HDACs). HDAC4 is highly expressed in neurons and is usually trapped in cytosol. However, tightly regulated signal-dependent shuttling of this molecule between cytosol and nucleus occurs. Here, we studied the intracellular trafficking of HDAC4 and regulatory mechanisms during stroke. HDAC4 translocated from the cytosol into the nucleus of neurons in response to stroke induced by middle cerebral artery occlusion (MCAO) in mice. Similar translocation was seen after oxygen-glucose deprivation (OGD) in cultured mouse neurons. Expression of nuclear-restricted HDAC4 increased neuronal death after OGD and worsened infarcts and functional deficits in mice following MCAO; however, expression of cytosolic-restricted HDAC4 did not affect outcome after ischemia. In contrast, HDAC4 knockdown with siRNA improved neuronal survival after OGD. Furthermore, expression of nuclear-restricted HDAC4 reduced the acetylation of histones 3 and 4 as well as the levels of pro-survival downstream molecules after OGD. Finally, genetic deletion of calcium/calmodulin-dependent protein kinase IV (CaMKIV) increased the nuclear accumulation of HDAC4 in MCAO model, while overexpression of CaMKIV reduced the levels of nuclear HDAC4 following OGD. When HDAC4 was inhibited, the neuroprotection provided by CaMKIV overexpression was absent during OGD. Our data demonstrate a detrimental role of the nuclear accumulation of HDAC4 following stroke and identify CaMKIV as a key regulator of neuronal intracellular HDAC4 trafficking during stroke.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Denton
authors.affiliation: Department of Neurology, University of Texas Health Science Center, Houston, TX, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, United States.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Li
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, United States.
authors.forename: Sharon
authors.initials: S
authors.lastname: Benashski
authors.affiliation: Department of Neurology, University of Texas Health Science Center, Houston, TX, United States.
authors.forename: Louise
authors.initials: L
authors.lastname: McCullough
authors.affiliation: Department of Neurology, University of Texas Health Science Center, Houston, TX, United States. Electronic address: jun.li.3@uth.tmc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
chemical_list: D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: CaMKIV; HDAC4; Stroke