Group: Seiser, Christian

Research Focus

Dynamic acetylation of histone proteins induces local changes in the chromatin structure and thereby controls important biological processes such as transcription, replication and DNA repair. Histone deacetylases (HDACs) remove acetyl groups from histones and other proteins and act as transcriptional co-regulators. Small molecule inhibitors of HDACs are used in anti-tumor therapy and for treatment of neurological disorders, parasitic and inflammatory diseases. Our research focuses on the class I deacetylases HDAC1 and HDAC2. We have originally identified mouse HDAC1 as a growth factor inducible gene in T cells (Bartl et al., 1997). HDAC1 gene disruption 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 leads to increased proliferation and reduced differentiation and is linked with a more malignant phenotype (Lagger et al., 2010). By using conditional HDAC knockout mice we have recently revealed distinct but overlapping functions of HDAC1 and HDAC2 enzymes during epidermal development and tumorigenesis (Winter et al., 2013), in neurogenesis (Hagelkruys et al., 2014) and in collaboration with Wilfried Ellmeier during T cell development (Boucheron et al.,2014).

Main Objectives

• We intend to dissect the catalytic and non-catalytic functions of HDAC1 and HDAC2.

• We will examine whether HDAC1 and HDAC2 are relevant targets for small molecules as anti-cancer drugs.

• We plane to analyse how post-translational modifications of these enzymes control the assembly, activity and recruitment of HDAC1/HDAC2 co-regulator complexes.

Content of Research

We use transgenic mice, embryonic stem cells and haploid human tumor cells as model systems and RNA-seq, ChIP-seq, CRISPR-Cas and mass spectrometry as tools for the characterization of the biological function of mammalian class I HDACs.