Intracellular trafficking of histone deacetylase 4 regulates long-term memory formation.

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.

Overexpression of beta-catenin is responsible for the development of portal hypertension during liver cirrhosis.

beta-catenin functions as both a structural protein and a transcriptional activator. In this study, we examined the expression of beta-catenin in human cirrhotic livers, and administered adenoviruses carrying the beta-catenin or DeltaTCF4 genes to cirrhotic rats to investigate the role of beta-catenin in the development of liver cirrhosis development. beta-catenin expression was associated with liver cirrhosis development in cirrhotic human and rat liver. beta-catenin adenovirus was capable of accelerating cirrhosis progress but this progression was unaffected by administration of DeltaTCF4 adenovirus. beta-catenin was mainly located in the intercellular regions between liver cells and was highly concentrated in the hepatic sinusoid wall, where alpha-smooth muscle actin (SMA) was also mainly distributed. The binding of beta-catenin to alpha-SMA was also increased in cirrhotic liver. Portal vein blood pressure was significantly increased in the group administered beta-catenin adenovirus, but not in that receiving DeltaTCF4 adenovirus. These results suggest that high concentrations of beta-catenin at the hepatic intercellular membrane and the hepatic sinusoid wall contribute to hepatic hyperpiesia in liver cirrhosis patients. beta-catenin functions as a structural molecule, but not as a signaling molecule, during liver cirrhosis development.