title: Intracellular trafficking of histone deacetylase 4 regulates long-term memory formation.
abstract: Histone acetylation is important for gene transcription, which is controlled by the balance between two kinds of opposing enzymes: histone acetyltransferases and histone deacetylases (HDACs). HDACs repress gene transcription by decreasing histone acetylation levels. Our hypothesis was that shuttling of Class II HDACs, such as HDAC4, between the nucleus and cytoplasm is critical for its function. We constructed mutants of mammalian HDAC4 that had different cellular locations and checked their function during memory formation using Caenorhabditis elegans as a model. The deletion of hda4, a homolog of HDAC4, was able to enhance learning and long-term memory (LTM) in a thermotaxis model. Transgenic experiments showed that mammalian wild-type HDAC4 rescued the phenotype of hda4-deleted worms but impaired LTM formation in wild-type worms. The cytosol-localized HDAC4 mutant was not able to alter the phenotype of knock-out worms but led to enhanced LTM formation in wild-type worms similar to hda4-deletion mutants. Constitutive nuclear localization of HDAC4 rescued the phenotype of deletion worms similar to wild-type HDAC4 but had no effect on wild-type worms. These results support our hypothesis that HDAC4's biological function is regulated by its intracellular distribution.
authors.affiliation: The Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Wang
authors.forename: Li-Cheng
authors.initials: LC
authors.lastname: Cheng
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Pan
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Wang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology*; D057567:Memory, Long-Term / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D040681:Structural Homology, Protein
chemical_list: D029742:Caenorhabditis elegans Proteins; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases