The nucleosome, a complex of 147 base-pairs of DNA with eight histone proteins, must protect its DNA, but, at the same time, allow on-demand access to it when needed by the cell. The exact mechanism of the control, to understanding modulation of gene expression and, ultimately, epigenetics, remain unclear. We use basic physics to gain insights into the problem.
One key conclusion is that at physiological conditions the nucleosome complex is close to the phase boundary separating it from the “unwrapped" states where the DNA is more accessible. A small drop in the positive charge (e.g. through acetylation of a lysine) of the globular histone core can significantly lower the DNA affinity to the core, and thus increase DNA accessibility. The findings suggest that charge-altering post-translational modifications in the histone core might be utilized by the cell to modulate accessibility to its DNA at the nucleosome level. The property of being on the “phase boundary” between loose and condensed states also appears to apply to higher order chromatin structures such as nucleosome arrays. A multi-state atomistic model of the nucleosome explores virtually all possible charge-altering post-translational modifications (PTMs) in the globular histone core. The model reveals a rich and nuanced picture: the effect of PTMs varies greatly depending on location, including counter-intuitive trends such as a decrease of DNA accessibility upon acetylation of some of the lysine residue in the histone core. A detailed connection to transcription regulation in-vivo is made, laying the foundation for a new field: ``Physical Epigenetics”.
Speaker Bio:
Alexey Onufriev received his undergraduate degree in biophysics from the Moscow Institute of Physics and Technology, Russia in 1991. After graduation, he joined the theoretical biophysics group at Lebedev Physical Institute in Moscow, where he worked on mathematical modeling of ATP synthesis and issues of irreversibility in Quantum Mechanics. Following the untimely demise of the Soviet Union, Alexey left for the US to continue as a Ph.D. student at Brown University, focusing on computational condensed matter physics. He had received post-doctoral training in computational chemistry and molecular biophysics from Duke University and then at the Scripps Research Institute in San Diego.
In 2003 Alexey joined Virginia Tech as an assistant professor. Now he is a professor in several departments, including Computer Science, Physics, Biomedical Engineering and Mechanics. He is also affiliated with the graduate program in Genetics, Bioinformatics, and Computational Biology.
His interdisciplinary research group works at the interface of physics, biology, and computer science. The group develops and uses computational methods to understand dynamics and function of bio-molecular systems. A particular focus of Onufriev's research has been the development of solvent models. He also worked on condensation of nucleic acids and chromatin.
Physical Epigenetics, that is the use of physics-based approaches to understand epigenetics, is among his latest interests.