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Heinz Fischer/Christian Seiser

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Research Focus

Epigenetic mechanisms control the proliferation and differentiation of mammalian cells. Our research focussed on the role of DNA methylation and histone acetylation in development and disease.     
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. 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 previously 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, Hagelkruys et al., 2016) and in collaboration with Wilfried Ellmeier during T cell development (Grausenburger et al. 2010, Boucheron et al., 2014). We have recently generated a genetic tool box to characterize individual catalytic functions of class I HDACs and have systematically identified histone and non-histone acetylation targets of HDAC1, HDAC2 and HDAC3 (Hess, Moos et al., 2022) and have identified a new HDAC1/GSE1-containing complex with function in DNA damage response (Vcelkova et al., 2023).  
In a new project (FWF grant P37241-B) we aim to will investigate a novel nearly unexplored role of HDAC1: the regulation of lipid metabolism in the skin. This will be approached by using cellular models as well as a newly developed HDAC1 mouse line that targets specifically the catalytic activity of HDAC1 in the skin.
Methylation of DNA is the most important epigenetic mechanism in mammalian cells. It not only controls cell-specific gene expression but prevents the activation of transposons. We study the impact of DNA methylation on mammalian development by using conditional knockout mice for the maintenance DNA methyltransferase DNMT1. We have recently demonstrated that epidermal loss of DNMT1 results in transposon derepression, formation of micronuclei autoinflammation and pathological changes in the skin (Beck, Fischer et al. 2021).

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 for the treatment of cancer and immunological diseases.
  • We plan to elucidate the role of the enzymatic function of HDAC1 in cutaneous lipid metabolism.
  • We aim to analyze the impact of DNA methylation on cell differentiation, gene expression and genome integrity.

Content of Research
We use transgenic mice, keratinocytes, sebocytes 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.