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Modeling Protein Target Search in Human Chromosomes
Umeå University, Faculty of Science and Technology, Department of Physics.ORCID iD: 0000-0002-0544-9793
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Umeå University, Faculty of Science and Technology, Department of Physics.ORCID iD: 0000-0003-3174-8145
2021 (English)In: Physical Review Research, E-ISSN 2643-1564, Vol. 3, no 1, article id 013055Article in journal (Refereed) Published
Abstract [en]

Several processes in the cell, such as gene regulation, start when key proteins recognize and bind to short DNA sequences. However, as these sequences can be hundreds of million times shorter than the genome, they are hard to find by simple diffusion: diffusion-limited association rates may underestimate in vitro measurements up to several orders of magnitude. Moreover, the rates increase if the DNA is coiled rather than straight. Here we model how this works in vivo in mammalian cells. We use chromatin-chromatin contact data from Hi-C experiments to map the protein target-search onto a network problem. The nodes represent DNA segments and the weight of the links are proportional to measured contact probabilities. We then put forward a diffusion-reaction equation for the density of searching protein that allows us to calculate the association rates across the genome analytically. For segments where the rates are high, we find that they are enriched with active gene starts and have high RNA expression levels. This paper suggests that the DNA's 3D conformation is important for protein search times in vivo and offers a method to interpret protein-binding profiles in eukaryotes that cannot be explained by the DNA sequence itself.

Place, publisher, year, edition, pages
American Physical Society , 2021. Vol. 3, no 1, article id 013055
National Category
Other Physics Topics
Identifiers
URN: urn:nbn:se:umu:diva-164023DOI: 10.1103/PhysRevResearch.3.013055ISI: 000608675400003Scopus ID: 2-s2.0-85101603294OAI: oai:DiVA.org:umu-164023DiVA, id: diva2:1360539
Note

Originally included in thesis in manuscript form with title "Modelling Protein Target-Search in Human Chromosomes".

Available from: 2019-10-14 Created: 2019-10-14 Last updated: 2023-03-24Bibliographically approved
In thesis
1. My first-passage: target search in physics and biology
Open this publication in new window or tab >>My first-passage: target search in physics and biology
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Random walks and diffusing particles have been a corner stone in modelling the random motion of a varying quantity with applications spanning over many research fields. And in most of the applications one can ask a question related to when something happened for the first time. That is, a first-passage problem. Typical examples include chemical reactions which can not happen until the constituents meet for the first time, a neuron firing when a fluctuating voltage exceeds a threshold value and the triggering of buy/sell orders of a stock option. The applications are many, which is why first-passage problems have attracted researchers for a long time, and will keep doing so. In this thesis we analyse first-passage problems analytically.

A stochastic system can always be simulated, so why bother with analytical solutions? Well, there are many system where the first passage is improbable in a reasonable time. Simulating those systems with high precision is hard to do efficiently. But evaluating an analytical expression happens in a heart beat. The only problem is that the first-passage problem is tricky to solve as soon as you take a small step away from the trivial ones. Consequently, many first-passage problems are still unsolved.

In this thesis, we derive approximate solutions to first-passage related problems for a random walker and a diffusing particle bounded in a potential, which the current methods are unable to handle. We also study a continuous-time random walker on a network and solve the corresponding first-passage problem exactly in way that has not been done before. These results give access to a new set of analytical tools that can be used to solve a broad class of first-passage problems.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2019. p. 55
Keywords
first-passage, mean first-passage time, mean first-arrival time, random walk, diffusion, zero-crossing, persistence, survival probability, network, resetting
National Category
Other Physics Topics
Research subject
Theoretical Physics
Identifiers
urn:nbn:se:umu:diva-164025 (URN)978-91-7855-109-5 (ISBN)
Public defence
2019-11-08, N410, Naturvetarhuset, Umeå, 09:00 (English)
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Supervisors
Available from: 2019-10-17 Created: 2019-10-14 Last updated: 2019-10-16Bibliographically approved

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Nyberg, MarkusStenberg, PerLizana, Ludvig
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