Deciphering how and where small molecules of biological and therapeutic importance interact with genomes

• Applicant: Dr. Jonas Feldmann
• Subject Area: Biochemistry ; General Genetics and Functional Genome Biology ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549906483

Unravelling the fundamental structure of chromatin is paramount to decipher the mechanisms that regulate DNA function and to understand therapeutic approaches. Despite advancement in genome sequencing and chromatin biology, knowledge about genomic binding sites and interaction modes with small molecules remains limited. These interactions are versatile and can include DNA intercalators, DNA motif binder, and small molecules that bind DNA-associated proteins. Understanding these interactions is essential to further unravel regulatory processes, such as gene regulation, replication, transcription, DNA repair, and chromatin remodeling. Moreover, mapping small molecule binding sites accelerates the development of novel drugs and investigation of disease-related mechanisms. Abnormal interaction pattern could indicate certain dysfunctions and diseases, thereby advancing diagnostics. While numerous methods for mapping DNA-protein interactions have been established, methods for identifying DNA-small molecule interactions are rather scarce. Their sensitivity is severely limited compared to protein mapping methods, and the required number of cells is accordingly high. Moreover, studying DNA-small molecule interactions within live or single cells remains challenging, and mapping interactions of different molecules simultaneously has been unattainable. To solve some of these challenges, I propose a novel method for mapping DNA-small molecule interactions that outperforms and expands the scope of available technologies. Unlike available methods that employ a variety of biomolecules, including antibodies, to recruit an endonuclease (Tn5 transposase), I will covalently link this enzymatic complex to small molecules via click chemistry. The direct and customized Tn5 recruitment will not only obviate the need for other biomolecules but may also enhance the overall sensitivity. The final protocol will be time saving and may improve technical reproducibility. Furthermore, implementation of drug-specific barcodes will facilitate mapping of different small molecules simultaneously. This co-mapping strategy will unravel synergistic effects of different drugs and allow to study their combination for treating cancer or other complex diseases. These experiments have not been feasible with available technologies yet, making them a significant innovative leap forward.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Dr. Shankar Balasubramanian