Alladi Ramakrishnan Hall

Active Polymer Physics in Genetic Material Regulation

Rakesh Das

MPI-PKS Dresden

The dense packing of the polymeric genetic material, chromatin, along with mesoscopic condensates of regulatory biomolecules inside a typical eukaryotic cell nucleus presents a physical challenge for processing genetic information within a biologically relevant timescale. The non-random spatiotemporal organization of the subnuclear material is essential for overcoming this challenge [1]. However, the physical principles regulating the subnuclear organization remain elusive. I will present our recent investigations into how active perturbation, arising from various subnuclear molecular actions, affect this organization.

We developed a computational framework modelling chromatin as a coarse-grained block copolymer. The polymer is perturbed by a non-localized active mechanism mimicking the action of the Topoisomerase-II enzyme. Using a self-developed GPU-based parallelized code, we demonstrate that active perturbation phase separates the polymer (into euchromatic and heterochromatic regions) and gives rise to an emergent anisotropic phase. An equilibrium mean-field theory fails to capture the emergent physics, underscoring the crucial role of activity [2].

Combining this active polymer framework and a new theoretical model, we further investigated the dynamics of a tracer—representing an arbitrary biomolecular condensate—within the active chromatin medium. We show that the tracer dynamics can be described by a combination of three modes, each mode being linked to different physical aspects of the embedding medium. The activity enhances the tracer dynamics through a slow mode associated with chromatin-mesh remodelling. This provides new insights into how global active perturbations facilitate target-search processes within the complex polymeric medium [3].

These studies offer new insights into the active self-organization of soft and living matter. Since enzymatic activity correlates with processes like aging and cell cycle, our studies may elucidate the role of activity in cell state-specific genome regulation.

References:

1. Job Dekker et al., The 4D nucleome project, Nature 549, 219 (2017).

2. RD, Takahiro Sakaue, G. V. Shivashankar, Jacques Prost, and Tetsuya Hiraiwa, How enzymatic activity is involved in chromatin organization, eLife 11, e79901 (2022).

3. RD, Takahiro Sakaue, G. V. Shivashankar, Jacques Prost, and Tetsuya Hiraiwa, Chromatin remodeling due to transient-link-and-pass activity enhances subnuclear dynamics, Phys. Rev. Lett. 132, 058401 (2024).