Artem Efremov Lab

Development of a numerical algorithm for predicting the mesoscale organization of the cell genome based on the physicochemical properties and architecture of individual nucleoprotein complexes. Discovery of the piezoelectric behavior of the cell nucleus and its potential role in nuclear organization

• Date: 2019
• Institution: Shenzhen Bay Laboratory (China), Mechanobiology Institute (Singapore)
• Authors: N. O. Alieva, A. K. Efremov, S. Hu, D. Oh, Z. Chen, M. Natarajan, H. T. Ong, A. Jegou, G. Romet-Lemonne, J. T. Groves, M. P. Sheetz, J. Yan and A. D. Bershadsky
• Aim of study: DNA-architectural proteins play a major role in organization of chromoso-mal DNA, packaging it into chromatin whose spatial conformation is determined by an intricate interplay between the DNA-binding properties of architectural proteins and physical constraints imposed on the DNA by a tight nuclear space. Yet, the exact effect of the cell nucleus size on DNA-protein interactions and chromatin structure currently remains obscure. Furthermore, there is even no clear understanding of molecular mechanisms responsible for the nucleus size regulation in living cells. To find answers to these questions, I developed a semi-analytic method based on a combination of polymer field theory and transfer-matrix calculations, which allowed me to evaluate physical forces exerted to the nuclear envelope by different cell components and to study their contribution to the nucleus size regulation and chromatin organization.

Major results: Using the developed method it was shown that the nucleus size is mainly determined by the difference between the surface tensions of the nuclear envelope and the endoplasmic reticulum membrane, as well as the osmotic pressure exerted by cytosolic macromolecules on the nucleus. In addition, the model demonstrated that the cell nucleus functions as a piezoelectric element, changing its electrostatic potential in a size-dependent manner. This effect has been found to have a profound impact on stability of nucleosomes, revealing a previously unknown link between the nucleus size and chromatin structure and providing new insights into the potential role of nuclear organization in shaping the cell response to environmental cues.

Contribution to the research field: By creating a general theoretical framework describing the packaging of chromosomal DNA in the nuclei of living cells that takes into account the main physical forces involved in nuclear organization, a long missing link responsible for the experimentally observed correlation between the cell and nucleus volumes has been identified and described in detail. Furthermore, a previously unknown effect of the nucleus size on chromatin structure and organization has been predicted in the study. The corresponding publication was selected as a cover article of Biophysical Journal.