Enzymatic and non-enzymatic functions of HDAC1 and HDAC2

Histone deacetylases (HDACs) are crucial regulators of chromatin structure and gene expression. Their enzymatic activity results in local compaction of chromatin and thereby in reduced accessibility of specific genes. The closely related class I deacetylases HDAC1 and HDAC2 are components of the same multiprotein co-repressor complexes and control cell cycle progression, proliferation and differentiation of mammalian cells. Therefore these enzymes are potential targets for small molecule inhibitors used in the treatment of cancer and neurological disorders. In addition to their catalytic activity HDAC1 and HDAC2 have been recently shown to have also non-catalytic functions such as stabilization of specific co- repressor complexes. We have recently established novel transgenic mouse models that allow dissecting catalytic and non-catalytic functions of histone deacetylases. In this project we will use a mixture of genetic, biochemical and cell biological approaches to understand the contribution of catalytic and non-catalytic functions of mammalian HDACs to the control of cellular proliferation and differentiation during development and in disease. We will investigate the function of HDAC1 and HDAC2 activities in three settings: (1) during the development of the mouse brain (2) for self-renewal and differentiation of mouse embryonic stem cells (3) in a murine skin cancer model The results of this study will have important implications for disease biology, in particular cancer research and therapy of neurological disorders and for stem cell research.

Histone deacetylases (HDACs) are crucial regulators of chromatin structure and gene expression. Their enzymatic activity results in local compaction of chromatin and thereby in reduced accessibility of specific genes. The two deacetylases HDAC1 and HDAC2 have related functions and control proliferation and differentiation of mammalian cells. Therefore, these enzymes are potential targets for drugs used in the treatment of cancer, immunological and neurological disorders. To ask if the catalytic activity of HDAC1/HDAC2 is a relevant drug target, we have established novel transgenic mouse models and genetically modified tumor cell lines expressing inactive version of HDAC1 and HDAC2. In this project we have used a mixture of genetic, biochemical and cell biological approaches to understand the contribution of catalytic and non-catalytic functions of mammalian HDACs to the control of cellular proliferation and differentiation during development and in disease. We have shown in this project that: (1) genetically induced HDAC1 and HDAC2 enzyme inactivation has a stronger effect than the corresponding deletion of the gene (2) HDAC2 activity is crucial for proper embryonic development (3) HDAC1 and HDAC2 inactivation mimics treatment with HDAC inhibitors better than the respective knockouts in tumor cells This study reveals novel approaches for the analysis of the impact of HDAC1 and HDAC2 in cancer therapy and treatment of immunological and neurological disorders.