Epigenetische Einflüsse auf die Genomstabilität bei der Homöostase von Säugetieren

• Applicant: Robert Hänsel-Hertsch, Ph.D.
• Subject Area: Cell Biology ; Toxicology, Laboratory Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496650118

This project will elucidate epigenetic mechanisms promoting genome instability when tissue homeostasis declines with age and under physiological stress. We discovered elevated G-quadruplex (G4) DNA secondary structure formation in mutated highly transcribed gene regulatory regions of cancer, suggesting dysregulated G4 DNA regions as promoter of genome instability. We have and continue to gather evidence that dysregulated G4s emerge before cancer development in physiologically aged murine tissues and rapidly aged murine and human models. We hypothesize here that dysregulated G4 secondary structure formation may promote genome instability and heterostasis in aged and stress-induced tissues of rodent models. To address this and determine related mechanisms, we will employ our newly developed genome-wide multiomics technology to jointly map epigenetically linked DNA breakage beyond association. To identify epigenetic regulators that promote an increase in epigenetically linked DNA breakage in tissues of our rodent models, we will use computational predictions and experimental associations of our multiomics data with existing data sets. We will further use proximity ligation proteomics to directly link regulatory factors to epigenetically linked DNA breakage and validate these findings by genetic loss-of-function studies in C. elegans.

• DFG Programme: Research Units
• Subproject of: FOR 5504: Physiological causes and consequences of genome instability