Epigenetics of heart failure: the interdependency of DNA methylation and class II histone deacetylases

Aberrant epigenetic modifications like hypermethylation of promoter CpG islands are a common hallmark in cancer. Whether such modifications are also involved in the development of cardiovascular diseases, the most frequent cause of death in industrialized countries, is largely unclear. Histone acetylation/deacetylation is another layer of epigenetic modifications. Importantly, class II histone deacetylases (HDACs) are not only key players of cardiac growth but also in the development of heart failure. However, their direct target genes are still unknown. Class II HDACs are remarkably signal-responsive and shuttle between the cytosol and the nucleus. There, they interact not only with other histone deacetylases but also directly and indirectly with histone and DNA methyltransferases.

In collaboration with the group of Dr. Johannes Backs, Internal Medicine III of the University Heidelberg, we aim at the identification of novel, epigenetically deregulated heart failure target genes using state-of-the-art technologies like Methyl-CpG immunoprecipitation, microarray analysis, mass spectrometry, Next Generation Sequencing, mouse genetics (existing HDAC knockout mice) and experimental heart failure mouse models. The role of these genes for cardiomyocyte growth and function will then be elucidated by cellular and animal-based studies. Studies on protein-protein interaction will be used to understand the interplay between class II HDACs and distinct DNA methyltransferases and demethylases.

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• Dr. Johannes Backs, Internal Medicine III of the University Heidelberg