In human cells, a
meter-long DNA is condensed inside a micrometer-sized cell nucleus.
Simultaneously, the genetic code must remain accessible for its replication and
transcription to functional proteins. Such plasticity of the genome is
maintained by dynamic folding and unfolding of DNA-protein spools called
nucleosomes. It is unclear, however, how this process is controlled when
multiple nucleosomes stack on top of each other and form compact chromatin
fibers. This is particularly important since nucleosomes are rarely present in
isolation inside a densely packed cell nucleus. Therefore, the aim of this
thesis was to increase the understanding of the chromatin fiber structure and
its dynamics. Knowing these details would provide many new insights into the
mechanisms of gene expression (epigenetic regulation) which, upon malfunction,
may cause severe diseases. The presented work consists of an experimental
approach involving the application of single-molecule force spectroscopy, and
makes use of theoretical modelling based on statistical mechanics. By using
magnetic tweezers, we stretched and twisted individual chromatin fibers
reconstituted in vitro in order to unfold its nucleosomes. These studies show
that folding of nucleosomes into chromatin fibers opens up a plethora of
regulatory pathways for controlling the level of DNA organization in cells.This work was supported by the Netherlands Organisation for Scientific Research (NWO/OCW), as part of the Frontiers of Nanoscience program, and by the NWO-VICI Research Program Project 680-47-616.Biological and Soft Matter Physic