Dissection of in vivo functions of HDAC-6 and HDAC-1

Protein post-translational modifications play important roles in almost all biological processes. Those modifications
extend the biological complexity based on primary amino acid sequence and have dramatic impact on protein's
structure and functions. Specially, acetylatlion on histone N-terminal tails has been extensively studied and shown to
be involved in the regulation of chromatin structure and functions. The acetylatlion not only directly influences the
packaging of the chromatin but also provides new interaction platforms and signals for other chromatin-interacting
proteins, complexes, and activities. Moreover, increasing numbers of nonhistone proteins have been shown to be
regulated by acetylation/deacetylation. To understand in vivo role of histone and protein acetylation, we started to
investigate two histone deacetylases, HDAC-6 and HDAC-1. For this a variety of techniques were used including gene
targeting in mice.
In the introduction part the general definition and contents of epigenetics are presented. Then, various histone
modifications and their in vivo functions will be summarized. Specially, the acetylation/deacetylation of histones and
nonhistone substrates and their regulation by histone acetyltransferases (HATs) and histone deacetylases (HDACs)
are discussed. Finally, the clinical aspects of protein acetylation are considered.
The result section can be divided into four parts. First, we identified HDAC-6 as a novo tubulin deacetylase in vitro and
in vivo. Second, mainly based on experiments based on HDAC-6, we analyzed the structural basis of the histone and
tubulin deacetylation reaction and proposed a model for general protein deacetylation reaction. In the third part, we
generated HDAC-6 deficient mice and cells and have begun to characterize them. Finally, we presented ongoing
results on the generation of HDAC-1 floxed mice and HDAC-1 deficient cells.