Role of mouse histone deacetylase 1 for proliferation, differentation and development

Reversible histone acetylation induces changes in the chromatin structure and thereby modulates transcription in eukaryotic cells. Histone acetyltransferases and histone deacetylases control the dynamic acetylation on N-terminal tails of core histones. Histone deacetylase 1 (HDAC1) is a nuclear protein that belongs to a large family of evolutionary conserved enzymes catalyzing the removal of acetyl residues from histones and other proteins. HDAC1-mediated transcriptional regulation in mammalian cells was shown to be involved in a variety of biological processes including proliferation, cell cycle progression and differentiation. By disruption of the murine HDAC1 gene we have previously shown that HDAC1 is required for embryonic development. HDAC1 was identified as a major deacetylase in embryonic stem (ES) cells and loss of HDAC1 was shown to result in induced expression of the CDK inhibitors p21 and p27 and impaired proliferation. In this project we will analyze the function of mouse HDAC1 in development and proliferation in more detail. We will investigate the developmental defects in the absence of HDAC1 by marker analysis of HDAC1 null embryos and embryoid bodies. A selection of potential HDAC1 target genes will be analyzed by chromatin immunoprecipiation experiments. Furthermore, we will test whether reintroduction of HDAC1 wildtype protein and specific mutants will revert the phenotype of HDAC1 null cells. In addition, we will examine whether additional deletion of the genes for p21, p27 or Gcn5 can rescue the HDAC1 null phenotype. To investigate the role of HDAC1 in specific cell types or tissues we will perform a conditional HDAC1 KO analysis. In collaboration with other research laboratories we plan to analyze the function of HDAC1 in testis, B cell and T cell development.

In this project we analyzed how the packaging of our genetic material affects the expression of mammalian genes. Histone deacetylase 1 (HDAC1) is a cellular factor that induces the more efficient packaging of our genetic material, the DNA, thereby reducing the expression of specific genes. Our data disclose an important role of HDAC1 as regulator of gene expression and cellular proliferation. For these studies we had isolated embryonic stem cells from HDAC1-deficient mice. In the absence of HDAC1 several hundreds of genes are induced in their expression demonstrating a crucial role of HDAC1 as transcriptional repressor. On the other hand, a significant number of genes was found to be reduced in their expression levels. This is a surprising finding and sheds some new light on the role of histone deacetylases in the regulation of our genes. Furthermore, by targeted deletion of the HDAC1 function in various cell types we could show that tumor cells cease to proliferate in the absence of HDAC1. In contrast, other cell types such as T cells show even higher proliferation rates. Our findings suggest that specific inhibitors that preferentially interfere with the activity of HDAC1-type enzymes should have promise in treating cancer. This idea will be tested in mouse tumor model systems. Taken together this project provides new insights into the regulation of our genes. Given the differential sensitivity of normal cells and tumor cells towards loss of HDAC1, our data are relevant for the development of more specific anti-tumor drugs.