Intracellular Trafficking of Histone Deacetylase 4 Regulates Long-Term Memory Formation

College of Life Sciences, Hainan Normal University, Haikou, ChinaABSTRACTHistone acetylation is important for gene transcription, which is con-trolled by the balance between two kinds of opposing enzymes: histone ace-tyltransferases and histone deacetylases (HDACs). HDACs repress genetranscription by decreasing histone acetylation levels. Our hypothesis wasthat shuttling of Class II HDACs, such as HDAC4, between the nucleusand cytoplasm is critical for its function. We constructed mutants of mam-malian HDAC4 that had different cellular locations and checked their func-tion during memory formation using Caenorhabditis elegans as a model.The deletion of hda4, a homolog of HDAC4, was able to enhance learningand long-term memory (LTM) in a thermotaxis model. Transgenic experi-ments showed that mammalian wild-type HDAC4 rescued the phenotype ofhda4-deleted worms but impaired LTM formation in wild-type worms. Thecytosol-localized HDAC4 mutant was not able to alter the phenotype ofknock-out worms but led to enhanced LTM formation in wild-type wormssimilar to hda4-deletion mutants. Constitutive nuclear localization ofHDAC4 rescued the phenotype of deletion worms similar to wild-typeHDAC4 but had no effect on wild-type worms. These results support ourhypothesis that HDAC4’s biological function is regulated by its intracellu-lar distribution. Anat Rec, 00:000–000, 2011.