Project Details
Projekt
From fibers to the sea of nuclesomes: Computer simulations of the regulation of the spatial structure of Mbp chromatin domains in the nucleus
Applicant
Professor Dr. Gero Wedemann
Subject Area
General Genetics and Functional Genome Biology
Biophysics
Biophysics
Term
from 2019 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 422780392
In the nucleus of eukaryotes DNA is wrapped around histone proteins forming cylindrical units called nucleosomes. Nucleosomes are connected by linker DNA and form a bead-on-a-string like structure termed chromatin. In vitro chromatin adopts a fiber-like structure with a diameter of 30 nm while in general in vivo no such structure is observed. In the proposed research we will apply coarse-grained computer simulations of chromatin to elucidate conditions and properties of this folding, its regulation and the consequences of the changes. Linker DNA and the nucleosomes are modelled by cylindrical units interacting by elastic and electrostatic forces. Metropolis Monte Carlo and replica exchange methods are used to sample an ensemble of configurations in equilibrium. The conditions of high nucleosome density as in the nucleus will be mimicked in the simulations by modelling long nucleosome chains in the range of 1.5 Mbp and larger applying periodic boundary conditions. The spacing of the nucleosomes will be based on synthetic and real nucleosome positions from experiments. Fundamental spatial properties of the folding of higher order models will be extracted from these simulations. The model will be extended by potentials describing the loop-forming proteins cohesin and CTCF. The analysis of data from simulations will elucidate the distribution of contact probabilities as observed e.g. in chromosome conformation capture techniques and explain changes of the spatial structure by nucleosome repositioning and/or CTCF/cohesin depletion connected with gene regulation. Data from ATAC-Seq and Hi-C from healthy and malign cells provides information about transcription factor binding, chromatin accessibility and spatial structure. We will combine these data in models of large domains of chromatin, so called TADS, to elucidate cis- and trans-regulation mechanisms of genes and the deregulation of genes in malign cells.
DFG Programme
Priority Programmes
