DNA, the carrier of genetic information in our cells, is organized with the help of histone proteins as chromatin. Histone modifications affect the chromatin structure and thereby the of chromatin structures and associated with important biological processes such as transcription, replication and DNA repair. Our group is specifically interested in the role of histone deacetylases (HDACs) in development and disease. HDAC inhibitor treatment of tumor cells leads to cell cycle arrest, differentiation or apoptosis. Therefore, HDACs are potential targets for anti-tumor drugs and several HDAC inhibitors are currently tested in clinical trials. HDACs are considered as transcriptional co-repressors and 18 members of the HDAC family have been identified in mammalian cells.

We have originally identified mouse HDAC1 as growth factor inducible in cytolytic T cells (Bartl et al., 1997). HDAC1 gene disruption in mice leads to reduced proliferation and severe developmental problems resulting in embryonic lethality of HDAC1 knockout mice (Lagger et al., 2002). One crucial function of HDAC1 in the context of proliferation control is the repression of the CDK inhibitor p21/WAF1 suggesting a potential role of HDAC1 in tumorigenesis (Zupkovitz et al., 2010). Surprisingly, absence or reduced expression of HDAC1 in murine or human teratomas led to increased proliferation and reduced differentiation and was linked with a more malignant phenotype (Lagger et al., 2010). We are currently studying the function of HDAC enzymes in different cell types and tissues by using conditional HDAC knockout mice.

In a second project, we examine the role of histone phosphorylation during the activation of mammalian genes by stress and growth factors. The presence of histone H3 phosphorylation marks at the regulatory regions of several mammalian genes correlates with the induced expression of a dozens of target genes in mammalian cells. We have recently shown that 14-3-3 zeta can act as reader protein for S10- and S28-phosphorylated histone H3 (Winter et al., 2008a; Winter et al., 2008b). We have now identified the phosphatase PP2A as chromatin associated transcriptional repressor, which removes the active chromatin mark from specific target genes (Simboeck et al., 2010). In the near future, we plan to analyze the genome wide presence of H3 phosphorylation marks in mouse cells.

Bartl, S., Taplick , J., Lagger, G., Khier, H., Kuchler, K. and Seiser, C. (1997) Identification of mouse histone deacetylase 1 as a growth factor-inducible gene. Mol. Cell. Biol., 17, 5033-5043.

Lagger, G., O'Carroll, D., Rembold, M., Khier, H., Tischler, J., Weitzer, G., Schuettengruber, B., Hauser, C., Brunmeir, R., Jenuwein, T. and Seiser, C. (2002) Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. Embo J, 21, 2672-2681.

Lagger, S., Meunier, D., Mikula, M., Brunmeir, R., Schlederer, M., Artaker, M., Pusch, O., Egger, G., Hagelkruys, A., Mikulits, W., Weitzer, G., Muellner, E.W., Susani, M., Kenner, L. and Seiser, C. (2010) Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans. EMBO J, 29, 3992-4007.

Simboeck, E., Sawicka, A., Zupkovitz, G., Senese, S., Winter, S., Dequiedt, F., Ogris, E., Di Croce, L., Chiocca, S. and Seiser, C. (2010) A phosphorylation switch regulates the transcriptional activation of cell cycle regulator p21 by histone deacetylase inhibitors. J Biol Chem, 285, 41062-41073.

Winter, S., Fischle, W. and Seiser, C. (2008a) Modulation of 14-3-3 interaction with phosphorylated histone H3 by combinatorial modification patterns. Cell Cycle, 7, 1336-1342.

Winter, S., Simboeck, E., Fischle, W., Zupkovitz, G., Dohnal, I., Mechtler, K., Ammerer, G. and Seiser, C. (2008b) 14-3-3 Proteins recognize a histone code at histone H3 and are required for transcriptional activation. Embo J, 27, 88-99.

Zupkovitz, G., Grausenburger, R., Brunmeir, R., Senese, S., Tischler, J., Jurkin, J., Rembold, M., Meunier, D., Egger, G., Lagger, S., Chiocca, S., Propst, F., Weitzer, G. and Seiser, C. (2010) The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation. Mol Cell Biol, 30, 1171-1181.

Top Citations:

Lagger, et al. (2002) Embo J, 21, 2672-2681:  288

Doetzlhofer, et al. (1999) Mol.Cell.Biol., 8, 5504-11: 257

Bartl, et al. (1997) Mol. Cell. Biol., 17, 5033-5043: 102