Mechanics of condensed chromatin and its dependence on chromatin remodeling

• Applicants: Professor Dr. Felix Müller-Planitz; Professor Dr. Johannes Stigler
• Subject Area: Biophysics
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577467251

Chromatin provides the scaffold for the maintenance and propagation of hereditary information, and for the expression and regulation of genes. Chromatin possesses mechanical properties that vary drastically differ at different length scales. At the ~100 kbp-level, chromatin is mechanically fluid. It thereby allows access to molecular machines and provides an environment that enables dynamic regulatory contacts between distant genomic loci. The mechanical properties of chromatin are hence closely tied to its biological function. How the mechanical properties of chromatin are encoded at the molecular level remains poorly understood. Temporary nucleosome-nucleosome interactions certainly play a crucial role. A dynamic network of these inter-nucleosome interactions provides sufficient adhesive forces that allow chromatin to phase separate into biological condensates. The identity, strengths and lifetimes of the interactions remain obscure though. Importantly, the nucleosome organization of chromatin is also not static. Its composition and structure are constantly modulated by molecular processes, chiefly by ATP-dependent chromatin remodelers. These remodeling enzymes have the ability to slide nucleosomes and, as such alter the structure of chromatin at the molecular level. By this, they are predicted to also affect the material state of chromatin at the mesoscale. However, the connection between remodeling and chromatin mechanics is poorly understood. Remodelers also can affect the material state of chromatin simply through binding to chromatin. We have shown that the remodeler ISWI needs ATP hydrolysis to move through condensed chromatin. Failure to hydrolyze ATP leads ISWI to bridge two nucleosomes on neighboring chromatin fibers through multivalent binding, which causes massive mechanical hardening of chromatin. We have rationalized these findings with a "monkey-bar" movement model for ISWI. However, direct structural and functional evidence of the monkey-bar model is missing, and it is also unclear if monkey-bar behavior also pertains to remodelers other than ISWI. This project will use single-molecule methods, micromanipulation techniques, structural methods and molecular modeling to experimentally challenge the monkey-bar model. Furthermore, we will determine how the nucleosome architecture dictates chromatin mechanics and how active remodeling influences the mechanical properties of condensed chromatin. The results will provide a pioneering look into the fundamental link between remodeling, the molecular composition of chromatin and its biologically relevant physical properties at the mesoscale.

• DFG Programme: Research Grants