Nick Kinney, GBCB Doctoral Candidate, on "Chromosome-nuclear envelope interactions have multiple effects on chromosome folding dynamics in simulation"
Advisors: Dr. Igor Sharakhov, Dept of Entomology, VT
Dr. Alexey Onufriev, Dept of Computer Science and Applications, VT
Thursday, January 29, 4:00PM, VBI Conference Center, 1015 Life Science Circle
Abstract: It is well recognized that the chromosomes of eukaryotes fold into non-random configurations within the nucleus. In humans and fruit flies, chromosomes likely adopt a particular 3D configuration called the fractal globule (FG) ( 1 ) which has multiple biologically significant properties. However, the fractal globule is a metastable state which, over time, transitions to a less biologically favorable state called the equilibrium globule ( 2 ) . One of the key questions is how the FG state is stabilized in-vivo? We use simulations to study the effects of chromosome-nuclear envelope (Chr-NE) interactions on the dynamics of the fractal globule within a model of Drosophila melanogaster (fruit fly) interphase chromosomes. The computational model represents chromosomes as self-avoiding walks (SAW) bounded by the nuclear envelope (NE). Model parameters such as nucleus size, chromosome persistence length, and chromosome-nuclear envelope interactions are taken directly from experiment(3). Several key characteristics of the non-equilibrium FG state are monitored during each simulation’s progress: chromosome territories, intra-chromosomal interaction probabilities, loci specific diffusion constants, and presence of the Rabl (polarized) chromosome arrangement. Next, we compare the outcomes of simulations which include or exclude Chr-NE interactions. We find that Chr-NE interactions reinforce the non-equilibrium properties such as chromosome territories, high intra-chromosome interaction probabilities, and the Rabl chromosome arrangement. In addition, Chr-NE interactions affect loci specific and averaged chromosomal diffusion. Based on these results we conclude that the presence of Chr-NE interactions may delay the decay of the biologically relevant fractal globule state in vivo.
1. Sexton, T., Yaffe, E., Kenigsberg, E., Bantignies, F., Leblanc, B., Hoichman, M., Parrinello, H., Tanay, A. and Cavalli, G. (2012) Three-dimensional folding and functional organization principles of the Drosophila genome. Cell , 148 , 458-472 .
2. Mirny, L. (2011) The fractal globule as a model of chromatin architecture in the cell. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology , 19 , 37-51.
3. Pickersgill, H., Kalverda, B., de Wit, E., Talhout, W., Fornerod, M. and van Steensel, B. (2006) Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nat Genet , 38 , 1005-1014 .