Talks

The role of telomeres in cellular and organismal physiology including ageing and cancer is commonly appreciated. However, intriguingly, the molecular impact of telomeres in human cells has been largely limited to the subtelomeres (~10 Mb from telomeres). Questioning this paradigm we found telomere dependent molecular mechanisms affect chromatin across the genome defining functional outcomes ranging from tumor cell immunity to neurogenesis.

We investigate the role of compaction of chromatin domains in modulating search kinetics of proteins. Collapsed conformations of chromatin, characterised by long loops which bring distant regions of the genome into contact, and manifested structurally as Topologically Associated Domains (TADs) affect search kinetics of DNA associated transcription factors and other proteins. In this study, we investigate the role of the compactness of chromatin on the dynamics of proteins using a minimal model. Using analytical theory and simulations, we show that an optimal compaction exists for which the residence time of proteins on a chromatin-like polymer backbone is minimum. We show that while bulk diffusion is an advantageous search strategy for extended polymers, for highly folded polymer domains, intersegmental transfers allow optimal search. We extend these results to more detailed polymer models - using the Freely Rotating Chain model, a Lennard-Jones bead-spring polymer model, which approxi...

The three-dimensional organization of chromatin into domains and compartments leads to specific scaling of contact probability and compaction with genomic distance. However, chromatin is also dynamic, with active loop extrusion playing a crucial role. While extrusion ensures a specific spatial organization, how it affects the dynamic scaling of measurable quantities is an open question. In this work, using polymer simulations with active loop extrusion, we demonstrate that the interplay between the timescales of extrusion processes and polymer relaxation can influence the 3D organization of chromatin polymer. We point out this as a factor contributing to the experimentally observed non-trivial scaling of relaxation time with genomic separation and mean-square displacement with time. We show that the dynamic scaling exponents with loop extrusion are consistent with the experimental observations and can be very different from those predicted by existing fractal-globule models for chromat...

The organization of genome within the cell is essential for survival across all domains of life. The physical principles that govern genome organization remain elusive. Phase separation of protein and DNA has emerged as an attractive mechanism for reshaping and compacting the genome. In vitro studies have shed light on the biophysical principles of protein-DNA condensates driven by protein-protein and protein-DNA interactions. However, the role of DNA sequence and its impact on protein-DNA condensation remains elusive. Guided by experiments, we have developed a simple polymer-based model of protein-mediated DNA condensation that explicitly incorporates the influence of DNA sequence on protein binding. By employing coarse-grained Brownian dynamics simulations, we shed light on how DNA sequence affects the number, size and position of protein-DNA condensates. Comparing our simulation results with experimental data for the nucleoid-associated protein Lsr2 provides new insights into the me...

Bacterial chromosome segregation, ensuring equal distribution of replicated DNA, is crucial for cell division. During fast growth, overlapping cycles of DNA replication and segregation require efficient segregation of the origin of replication (Ori), which is known to be orchestrated by the protein families SMC and ParAB. I will discuss our approach using data-driven physical modeling to study the roles of these proteins in Ori segregation. Developing a polymer model of the Bacillus subtilis genome based on Hi-C data, we analyzed chromosome structures in wild-type cells and mutants lacking SMC or ParAB. Wild-type chromosomes showed clear Ori segregation, while the mutants were segregation deficient. The model suggests the dual role of ParB proteins, loading SMCs near the Ori and interacting with ParA enriched at the cell poles, is crucial for Ori segregation. ParB-loaded SMCs compact individual Ori and introduce an effective inter-sister repulsion. While both the ParB-bound Ori tracks ...

I will present our recent work on the role of DNA and RNA polymerases in driving the spatio-temporal dynamics of chromosome in higher eucaryotes using biophysical modeling and analysis of experimental data.