FUNCTIONAL CHARACTERIZATION OF HDAC1 AURORA-DEPENDENT PHOSPHORYLATION IN MAMMALIAN CELLS AND ZEBRAFISH DEVELOPMENT

Histone deacetylases (HDACs) are a class of modification enzymes that catalyze the removal of acetyl molecules from histone and non-histone substrates. Therefore, they play important roles in chromatin remodelling and gene expression control through regulation of histones, transcription factors, and chromatin-modifying enzymes. Class I HDACs, in particular HDAC1 and HDAC2, are ubiquitously expressed and are critical regulators of cell cycle progression, cellular proliferation and differentiation during development. Besides their subcellular localization and incorporation into multi-0subunit complexes, HDAC1 and HDAC2 can also be regulated by a plethora of post-translational modifications (PTM), which represent a complex “code” that modulates their catalytic activity, localization and complex assembly. Among the various PTMs that occur on HDAC1 and HDAC2 we identified a new mitotic-specific phosphorylation of the two enzymes driven by Aurora kinases A and B. By means of mammalian cells and zebrafish embryos, we dissected the biological role of HDAC1 Aurora-dependent phosphorylation during development, contributing to deciphering the PTM code of these deacetylases. Indeed, we demonstrated that this phosphorylation in vitro and in vivo partially and dynamically affects HDAC1 enzymatic activity. Moreover, we found that Aurora-driven phosphorylation of HDAC1 is critical for the maintenance of a proper proliferative and developmental plan in a complex organism and crucially regulates global histone acetylation levels in zebrafish development. Thus, affecting its activity on histone acetylation, HDAC1 mitotic phosphorylation acts as fine-tune regulator of proper cell cycle progression, probably by modulating the expression of genes directly involved in zebrafish development.