Universiteit Leiden

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Research project

Packaging and accessing DNA molecules

Our DNA molecules are packaged by proteins in compact structures. The aim of this project is to understand how modern gene editing techniques nevertheless get access to their target in the DNA.

Duration
2019  -   2022
Contact
Helmut Schiessel
Funding
NWO Klein NWO Klein

Our DNA molecules are packaged with the help of histone proteins into millions of nucleosomes, DNA spools with protein cores. The positions of the nucleosomes are not random but are influenced by the sequence-dependent elasticity and geometry of the DNA double helix. 

There are numerous examples of meaningful mechanical cues that have evolved on real genomes of various organisms. These mechanical signals constitute thus a second layer of information on our DNA, in addition to the classical layer of genetic information. 

This leads to many exciting new questions which can be answered with efficient computational methods that were developed recently in our group. Here we propose to focus on questions where the partial unwrapping of DNA from nucleosomes plays a crucial role. 

Nucleosomes

Specifically, we have two sets of questions: (1) How can DNA inside nucleosomes be accessed by proteins and how does this depend on the underlying base-pair sequence? (2) How does the base-pair sequence influence the higher order structures beyond single nucleosomes?

Question (1) is a physics question of fundamental importance in biology. Its urgency lies in the fact that the currently hottest tool in DNA biology, the genome-editing tool CRISPR-Cas9, has to deal with precisely this set of physical problems. 

An answer to question (2) is also needed urgently as the chromatin field lives currently in a state of confusion. The common textbook view, the chromatin fiber as the level of packaging beyond the nucleosome, has been under severe attack. 

With recent progress on larger scales (chromatin conformation capture, new polymer theories and simulations), this leaves a painful gap between the small and the large scales that we tend to close, at least partially, by caring about how base-pair sequence effects influence larger scale structures.

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