Dynamic Chromatin Structure and Proteomic Alterations of the adenoviral genome throughout the infection cycle

• Applicants: Professor Dr. Axel Imhof; Professor Dr. Gernot M. Längst
• Subject Area: Virology ; General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569053114

Context: Adenoviruses (AdV) are non-enveloped, double-stranded DNA viruses that cause self-limiting infections in immunocompetent hosts, while severe disease primarily affects immunocompromised individuals. Due to their low pathogenicity, adenoviruses are widely used as vectors in gene therapy, oncolytic therapy, and vaccine development, including during the COVID-19 pandemic. A key factor in their success is the efficient delivery and expression of their genome, though the molecular mechanisms behind this efficiency remain poorly understood. The objective of the DynCAPA project is to uncover the molecular basis of the efficient adenoviral genome transcriptional activation at the early stages of infection. Our preliminary work shows that transcription of the E1A gene is highly dependent on genome anchoring to cellular chromatin mediated by the terminal protein (TP) covalently bound at each extremity of the genome. We have three main objectives; i) elucidating the role of TP in adenoviral gene activation, ii) investigating the adenovirus host chromosome interaction sites and the dynamic changes in adenoviral and host chromatin structure and iii) characterising the mode of Terminal Protein - nucleosome interaction, and identifying the drivers behind transcriptional activation by conducting a dynamic, comprehensive analysis of the genome-associated proteome using targeted single-genome mass spectrometry. Our hypothesis is that Adenoviruses achieve highly efficient genome expression through the terminal protein targeting incoming genomes to a favorable intranuclear environment where changes in viral and/or cellular chromatin mediate the onset of viral gene expression. By systematically analyzing the underlying molecular interactions, we can uncover fundamental principles of viral chromatin dynamics that contribute to both adenoviral pathogenesis and their potential as therapeutic vectors. Additionally, our analysis will provide insights into viral adaptation and coevolution that may be applicable to other DNA viruses.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Professor Dr. Harald Wodrich