Chromatin is a long-range force generator that regulates plasma membrane tension and cell integrity independently of gene expression
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Primarily studied for its role in gene expression, chromatin organization is emerging as an important regulator of nuclear mechanics. Although the nucleus is in mechanical equilibrium with the cell, we do not know whether and how chromatin reorganization actively regulates the mechanical properties and downstream behaviors of cells. Here, we tested the hypothesis that as a dynamic crosslinked polymer, chromatin directly impacts cell mechanics independently of transcription by studying NETosis: a transcription-independent process where chromatin decompacts and the plasma membrane (PM) ruptures. Using high resolution microscopy and ATAC-see, we found that chromatin accessibility progressively increases during NETosis suggesting that chromatin binding proteins (CBPs) dissociate from chromatin during NETosis. To determine the identity and dynamics of these dissociated CBPs, we used fluorescent recovery after photobleaching to measure the mobility and localization of the linker histone H1, the nucleosomal histone H3 and the heterochromatin binding protein HP1α. We found that the mobile fraction of nuclear H1 increases during NETosis while fractions of HP1α and H3 diffuse outside of the nucleus suggesting that they become cytosolic osmolytes and potentially alter the mechanical state of cells. Consistently, we found that plasma membrane tension and cell volume increase as chromatin decompacts during NETosis. In non-NETing U2OS cells, we found that inducing chromatin decompaction increases plasma membrane tension, independently of the cytoskeleton, indicating a causal relationship between chromatin organization, cell volume and plasma membrane tension. Our findings reveal a novel non- genetic role of chromatin in cellular biophysics: regulating cell volume, PM tension, and thus, overall cell mechanics. Considering the critical role of cell mechanics in biological processes such as cell migration, proliferation and pathogen killing, our work broadens our understanding of how chromatin regulates cell physiology and pathology.
Significance Statement:
Chromatin organizes our DNA inside the nucleus and is important for gene expression. However, chromatin is also a polymer which can passively regulate the rigidity of the nucleus, but whether and how chromatin can actively regulate the mechanical properties of the whole cell remains unknown. Here, we leverage the immune process of NETosis to show that the organization of chromatin inside the nucleus actively regulates the volume and tension of cells. Our work establishes chromatin as a long-range force generator in cells, broadening our understanding of the roles of this crucial polymer network in cells and opening the door to new strategies for controlling the mechanical properties of cells as needed by their physiology.
