Diffusion Processes in the Interphase Cell Nucleus - Connections between Chromatin Structure, Chromatin Dynamics and Macromolecular Transport

Abstract

The metabolism of a living cell requires a permanent transport of various macromolecules. In the cell nucleus, this transport is accomplished by diffusion and takes place in a dense network of chromatin fibers. This work deals with connections between the structure of chromatin fibers, their dynamics and the diffusional transport of macromolecules in the cell nucleus. The chromatin fibers are represented on a Cartesian lattice, based on the model of a semi-flexible chain polymer. Using a Monte Carlo procedure, specific lattice chain conformations that correspond to chromatin fibers in interphase are generated. Thereafter, random walks simulate the macromolecular diffusion in the thus created chromatin network The influences of chromatin structure on the mobility of diffusing macromolecules are investigated, particularly those arising from the folding into spatially separated subvolumes of the cell nucleus. This folding principle is known as compartmentalization and can be induced by the formation of specific chromatin loops. The simulations show that the fiber structure governs the spatial distribution of chromatin on different length scales in the cell nucleus. A measure of inhomogeneity is introduced to connect the spatial distribution of chromatin to the diffusion coefficient, the anomaly parameter and the characteristic length scale of anomalous diffusion. The determinability of this measure of inhomogeneity with confocal microscopy and DNA sequence analyses is examined, and different models of diffusion in polymer systems are compared to the simulations. Further, the effects of chromatin dynamics and a high concentration of diffusing macromolecules on the diffusion behavior are analyzed. Chromatin dynamics enhances the accessibility of the chromatin network, particularly in the case of a high concentration of mutually obstructing diffusing macromolecules. The obstruction of individual diffusing macromolecules by chromatin fibers can be distinguished from the obstruction caused by other diffusing macromolecules in terms of diffusion coefficients and the characteristic length scales of anomalous diffusion. The dynamics of chromatin is only slightly decelerated by a high concentration of diffusing macromolecules. A high density of chromatin and the entanglement of chromatin fibers cause much greater deceleration.