The many roles of histone deacetylases in development and physiology: implications for disease and therapy

Abstract

Mammalian genomes encode eleven proteins of the classical histone deacetylase (HDAC) family. They are numbered HDAC1 to HDAC11 and can be classified into four distinct groups (class I, IIa, IIb and IV), which differ in structure, enzymatic function, subcellular localization and expression patterns. Class I HDACs (HDAC1, 2, 3 and 8) are ubiquitously expressed highly active enzymes which localize predominantly to the nucleus. Genetic deletion is lethal in all cases with phenotypes ranging from gastrulation defects to cardiovascular malformation. Class IIa HDACs (HDAC4, 5, 7 and 9) are signal-responsive transcriptional repressors that interact with the transcription factor myocyte enhancer factor 2 (MEF2) and have minimal enzymatic activity towards classical histone substrates, owing to a conserved amino-acid change in the catalytic pocket. Genetic deletion leads to superactivation of MEF2 with resulting phenotypes in the heart, skeleton and endothelial cells. HDAC6 and HDAC10 form the class IIb HDAC family, with HDAC6 being the main cytoplasmic deacetylase in mammalian cells. HDAC6 has numerous targets, including tubulin and intracellular chaperones. Genetic deletion of HDAC6 does not lead to an overt phenotype. HDAC11 is the sole member of the class IV HDACs. Little is known about its function. Genetic deletion of individual HDACs leads to surprisingly specific phenotypes. Analysis of the resulting mutants has shown that HDACs control specific gene expression programmes. One major challenge for the future will be to decipher the role of individual HDACs in specific disease processes and to develop isoform-specific inhibitors. It is expected that this will lead to a broader therapeutic window of HDAC inhibitors, and possibly to a clinical application in non-oncological disease states.