Research
I use molecular simulation to study the structure of chromatin (DNA) in the cell nucleus. My research seeks to understand how patterns of chemical modifications placed throughout the genome control 3D genome organization and gene expression, especially as it relates to the onset of disease.
The video on the right is an example snapshot from molecular simulation of an entire chromosome in a human cancer cell line, with inactive regions highlighted in red and regions primed for silencing highlighted in green.
What is Chromatin
The DNA in our body is so long that if stretched end to end, it would reach from the earth to the sun and back over 600 times. So, in order to fit in our tiny cells, it needs to wrap around histone proteins to form a chromatin fiber. Each histone core with the wrapped DNA is called a nucleosome, and they form what appear to be beads on a string. A video shown on the right shows two molecular models for a nucleosome: the model on the left represents the DNA (yellow) and the histone proteins (red/white/blue), while the model on the left represents the entire nucleosome as a simplified spheroid.
Chromatin has a code
In order to gain access to the DNA, nucleosomes are marked by small chemical modifications (methyl, acetyl etc). A vast array of regulatory proteins bind to different modifications in order to gain access to the genetic information. The pattern of these chemical modifications is called the epigenetic code. We want to understand how that code is interpreted, how it affects the three-dimensional structure of chromatin, and how that structure affects gene expression.
Physical simulations of chromatin
We use physical simulations of chromatin to reconstruct 3D genome structure from experimental data (Chromatin Conformation Capture). In the process, we determine the influence of each epigenetic mark on the 3D structure. Recently, there has been interest in the prospect of using CRISPR technologies to edit the locations of epigenetic marks. However, it is unclear how the epigenetic code should be edited to accomplish a desired change in gene expression. We are using molecular simulations to perturb the location of epigenetic marks in silico and predict the downstream effects in order to inform future experiments and potential therapeutic routes.
