Organization and dynamics of chromatin under perturbation

Spatial organization of chromatin inside the nucleus regulates the gene expression of that cell and determines its specific functionality. Starting from the nucleosomal scale (~10 nm, DNA duplex wrapping around histone octamer) to the nuclear scale (~6-10 micron), chromatin shows several modes of organization and those modes are generally dynamic in nature. There are growing number of experimental evidences showing that the chromatin organization and dynamics depend upon various mechanical signals that the nucleus receives from the extracellular and the extranuclear material. Also, various chemical agents (viz., enzymes) present in the system perturb the chromatin. Response of the chromatin to these mechanical and chemical perturbations determines the cell-state specific genome regulation. A comprehensive understanding of this phenomenology has its implication in say cellular aging, cancer research etc.

Recently, me together with my collaborators published an article (eLife 11:e79901 (2022)) showing how enzymatic activity affects chromatin organization. Using a computational model based on the concepts of polymer physics, we showed that mechanistic scheme of enzyme's activity, beyond consideration of just thermodynamic aspect of it, is critical in determining precise organization features of chromatin. In an extension to that work, we have prepared another manuscript (arXiv:2305.05521 [physics.bio-ph]) showing how activity-dependent modification of chromatic environment affects the dynamics of nuclear inclusions (e.g., Cajal body, nucleolus, PML body). Another project we are working on is to see the effect of histone tail modification (viz., methylation and acetylation) due to enzymes on the chromatin organization and its dynamics.

Self-assembly of biomolecular condensates and their dynamics

There are various types of biomolecular condensates inside cell that play critical roles in regulating biological reactions. For example, intranuclear condensates like Cajal bodies or PML bodies are involved in activities like RNA processing, transcriptional regulation, and antiviral defense. In the cytoplasm, condensates called stress granules appear in response to acute stress or in response to different diseases, viz., cancer, neurodegeneration. Usually these condensates are aggregates of several types of nucleic acids and proteins. Understanding the mechanism of the self-assembly of these condensates and their dynamics are important from therapeutic perspective. 

I have developed a computational model to describe dynamic self-organization phenomenon observed in my collaborators' experiment. Interestingly, we are finding that enzymatic activity of the cytoplasmic media is important in describing this phenomenology.   

Pattern formation in stress fibers and their dynamics

Stress fibers are higher order cytoskeletal structures comprising actin filaments, myosin motor filaments, and multiple types of passive cross-linking proteins. They are tension generating and load bearing structures helping a cell to respond to its extracellular mechanical environment. In general, the stress fibers  show a characteristic quasi-periodic organization pattern that correlates with its mechanosensitive property. In spite of several attempts to understand the emergence of this characteristic pattern in stress fibers theoretically, the research community is yet to reach a consensus mainly due to two reasons. First,  many of the theoretical studies consider assumptions that might not be realistic, and second, with the improvement of experimental techniques, theoreticians have more input to incorporate in their model studies. I am collaborating with experimentalists here at MBI to address the emergence of characteristic pattern in stress fibers and the correlation between this pattern and the dynamics of actin filaments observed in their experiments.