Day 2 :
University Medical Center, Germany
Bernd Kaina completed his PhD in Genetics from Universtity of Halle, Germany in 1976. He completed his Postdoctoral training at the Institute of Genetics in Gatersleben and continued his studies on DNA repair in the Department of Molecular Biology in Leiden, Netherlands and at the German Cancer Research Center in Heidelberg and, as a Heisenberg Fellow in the Department of Genetics of the Nuclear Research Center in Karlsruhe, Germany. In 1993, he obtained a full professorship at Institute of Toxicology of the University of Mainz and, since 2003; he acts as a Director of the Institute.
His research program focuses on MGMT and the regulation of repair genes, DNA damage signaling, genotoxicity, cancer formation and death of cells exposed to radiation, chemical genotoxins and anticancer drugs. In a translational research program, his group studies the mechanisms of resistance of glioma, melanoma and other cancer cell types to alkylating anticancer drugs.
To maintain genome integrity, DNA is subject to rigorous quality control and repair by proteins that recognize and remove harmful lesions, resulting from endogenous metabolic processes, microbiota activity, food-borne carcinogens and the exposure to external radiation and a plethora of man-made genotoxicants. Most of the DNA repair proteins are constitutively expressed while some others are inducible following genotoxic stress, contributing to adaptation to genotoxic stress. Most DNA repair pathways are complex, involving many enzymes and cofactors, which must be expressed in a balanced way in order to avoid uncoordinated and error-prone repair of DNA lesions.
The fine-tuned adaptive regulation of repair genes occurs on the level of transcription by promoter activation mediated by stress-inducible transcription factors. Some DNA repair genes, however, are subject to epigenetic regulation, which occurs notably in cancer cells.
The DNA repair gene MGMT is the best-studied example, frequently silenced by promoter hypermethylation in malignant brain tumours, which bears significant therapeutic implications. Moreover, DNA repair processes are involved in regulating gene activity on epigenetic level. The mechanisms of transcriptional and epigenetic regulation of DNA repair genes and biological consequences will be discussed.
Helmholtz Centre for Environmental Research– UFZ,Germany
Mario Bauer is a Specialist in environmental health at the Helmholtz Centre for Environmental Research. His scientific work is focused on identification and risk assessment of environmental and individual genetic dispositions accounting for environment-related diseases. He is an Expert in Toxicology and beyond his research interests he gives private lectures and seminars in environmental medicine at the University of Leipzig
Statement of the Problem: Epigenome-wide association studies (EWAS) revealed that independent of analyzed tissue, the degree of methylation changes by environmental or lifestyle factors are, in general, vanishingly small, although of high statistical significance. This small methylation difference determines the unfavorable need for greater cohorts when more genome-wide methylation sites will be analyzed. Besides, the biological relevance of methylation changes is still poorly understood.
Methodology & Theoretical Orientation: To evaluate the distribution of methylation changes in whole blood composed of different cell types, smoking-induced top-ranked and replicated single CpG sites were analyzed in separated cell types of healthy volunteers. Additionally, to get insight into the biological relevance of methylation changes, CpG-annotated gene and protein expressions were investigated.
Findings: First, methylation changes in blood are cell-type specific distributed. Smoking-induced methylation changes in whole blood (-21%) at cg05575921 (AHRR) rely on methylation changes (-55%) in granulocytes. Second, methylation shift of about 2% in whole blood at cg19859270 (GPR15) was found to be a cell type-specific CpG for GPR15-expressing cells. Tobacco smoking specifically induced the expansion of GPR15+ T cells as the major GPR15+ cell type in blood, thus provoked the methylation shift of the cell type specific cg19859270 in whole blood.
Conclusion & Significance: Addressing methylation changes to single cell types of the blood enable to perform EWAS on replicated smaller cohorts in contrast to the requirement of larger international consortium-based approaches considering the statistical needs of next generation sequencing based methods using whole blood. Thus, the identification of specific cell type responsible for the associated methylation shift in whole blood to the endpoint of interest has to be a prioritized approach in association studies especially for interpretation of molecular epigenetic signs in context of the diverse biological function of the tissue blood and for establishment of valuable biomarkers.
University of Stuttgart, Germany
Albert Jeltsch completed his PhD working on the mechanism of restriction endonucleases at University Hannover in 1994. Afterwards, he started to study DNA methyltransferases at Justus-Liebig University Giessen and at Jacobs University Bremen. Since 2011, he is a Professor of Biochemistry at the University Stuttgart.
He received the Gerhard-Hess award (DFG) and BioFuture award (BMBF). He has long standing expertise in “Biochemical study of DNA and protein methyltransferases, methyl lysine reading domains and in rational and evolutionary protein design”. His work has been published in more than 200 publications in peer reviewed journals and he is in the editorial boards of several journals.
DNA methylation is an important epigenetic modification that in concert with histone tail modifications is essential for gene regulation. In mammals, the DNA methylation patterns are set during embryogenesis and development but aberrantly altered during the onset and progression of diseases like cancer. The DNMT3A and 3B DNA methyltransferases play central roles in these processes, but it is still largely unknown, how DNA methylation patterns are generated and maintained in cells.
I will present novel concepts of the regulation of DNMT3A based on allosteric mechanisms and interacting proteins. Technologically novel DNA methylation patterns can be generated by targeted methylation using DNA methyltransferases fused to designed DNA recognition domains (zinc finger, TAL effector, or modified CRISPR/Cas9 complex). Targeted DNA methylation is a promising approach for durable gene regulation, with many applications in basic research and clinics.
I will present the progress in this field, mainly the application of CRISPR/dCas9 for targeted DNA methylation and discuss question like stability, methods to achieve an allele specific targeting and methylation.