IMSc Webinar

Theoretical modeling of epigenetic landscapes and embryonic development

Bivash Kaity

Department of Physics, IIT Bombay, Powai, Mumbai 400 076

Google meet link: evx-jvok-dmk

In this talk, I will focus on the dynamics of developmental pathways in different contexts through theoretical modeling and simulations. This presentation is structured as follows:

The effect of time-dependent drive and delayed feedback loop in two dimensional gene regulatory network:
Recent advances in reprogramming a differentiated cell back to a pluripotent
cell fate have rekindled interest in a quantitative understanding of the epigenetic landscape describing cellular differentiation. Reprogramming is a multistep process, involving multiple feedback loops. While the importance of feedback loops is well appreciated, most models assume instantaneous feedback, while biological feedback often involves a time delay between the signal and the response. In the present work, we propose a theoretical model based on a two-gene regulatory motif to investigate the role of time delay in the regulation of gene expression levels. In particular, we focus on the interplay between time-delayed feedback loops and time-dependent external chemical drive and their effect on dynamics. We observed that the concentration of the two transcription factors can undergo sustained oscillations and we speculate that this oscillatory state may provide an explanation of certain puzzling experiments on the reprogramming process. We also observe transdifferentiation-like behavior, where one differentiated state transitions to another without passing through an intermediate stem cell state.

The role of cytoskeleton in the spread of biological molecules in a syncytial Drosophila embryo:
Drosophila embryogenesis begins with nuclear division in a common cytoplasm forming a syncytial cell. Morphogen gradient molecules spread across nucleo-cytoplasmic domains to pattern the body axis of the syncytial embryo. The diffusion of protein molecules across this nucleo-cytoplasmic domain is potentially constrained by association with the components of cellular architecture. However, the extent of the restriction on the molecules has not been studied so far. In this study, we choose to focus on spatio-temporal dynamics of different molecules across the anterior-posterior axis of a syncytial Drosophila embryo. In particular, we observed the length scale associated with the spread of GFP molecules is higher than GFP-Tubulin. We conjecture that the GFP-Tubulin gradient is largely restricted as it interacts with the microtubule network and plasma membrane furrows. We also studied the gradient formation mechanism for the membrane-associated proteins (PH-PLC-CFP) that undergo reversible binding unbinding kinetics with the plasma membrane. We proposed a mathematical model incorporating heterogeneous binding and diffusion based on the Synthesis-Diffusion-Degradation model. Our analysis shows cytoarchitecture of the syncytial embryo plays a crucial role in the gradient formation mechanism and has implications for the spread of morphogen gradients.