(598b) Physical Modeling of the Spreading of Epigenetic Modifications through DNA Looping
AIChE Annual Meeting
2016 AIChE Annual Meeting
Food, Pharmaceutical & Bioengineering Division
Multiscale Systems Biology
Wednesday, November 16, 2016 - 3:33pm to 3:51pm
Loops in DNA occur at a range of length scales, from short DNA lengths on the order of 100 basepairs for the binding of regulatory proteins, to intermediate lengths of kilobases for chromosome folding, to long lengths of hundreds of kilobases for genetic recombination. It is important to recognize that different physics govern looping at different length scales. At short lengths, the rigidity of the DNA must be handled explicitly, whereas at long lengths, the overall chain dynamics dominate. Because of the range of length and time scales involved in the motion of DNA, gaining insight into looping dynamics has proved a particularly complicated pursuit. Previous theoretical studies have addressed the problem through physical modeling and simulation of DNA as a Rouse or semiflexible polymer and have obtained qualitative agreement with experimental results.
To build upon this research, we are working to develop a comprehensive kinetic model for the spreading of epigenetic modifications through DNA looping. We use both analytical theory and computer simulations to calculate the probabilities that various lengths of DNA will loop, and in both cases, we account for the dynamics of DNA looping over the entire range of relevant length scales. We consider the spreading of methyl marks along chromosomal DNA, as dictated by these looping probabilities and rates of methylation and demethylation. Given an initial methylation profile, we determine the steady-state probabilities that other sites will become marked. We examine the effects of the type of transfer (i.e. local vs. at-a-distance), the initial profile (i.e. presence or absence of a nucleation site), the overall topology of the DNA (i.e. linear vs. ring), and the DNA configuration (i.e. static vs. dynamic).