A Dynamical Model Reveals Gene Co-Localizations in Nucleus

Co-localization of networks of genes in the nucleus is thought to play an important role in determining gene expression patterns. Based upon experimental data, we built a dynamical model to test whether pure diffusion could account for the observed co-localization of genes within a defined subnuclear region. A simple standard Brownian motion model in two and three dimensions shows that preferential co-localization is possible for co-regulated genes without any direct interaction, and suggests the occurrence may be due to a limitation in the number of available transcription factors. Experimental data of chromatin movements demonstrates that fractional rather than standard Brownian motion is more appropriate to model gene mobilizations, and we tested our dynamical model against recent static experimental data, using a sub-diffusion process by which the genes tend to colocalize more easily. Moreover, in order to compare our model with recently obtained experimental data, we studied the association level between genes and factors, and presented data supporting the validation of this dynamic model. As further applications of our model, we applied it to test against more biological observations. We found that increasing transcription factor number, rather than factory number and nucleus size, might be the reason for decreasing gene co-localization. In the scenario of frequency- or amplitude-modulation of transcription factors, our model predicted that frequency-modulation may increase the co-localization between its targeted genes. Author Summary: Transcription is a fundamental step in gene expression, yet it remains poorly understood at cellular level. Textbooks are full of descriptions of promoter-bound transcription factors recruiting RNA polymerase, which initiates transcription before sliding along the transcription unit. However, increasing evidence supports the view that the DNA template bound with transcription factors slides through a relatively immobile RNA polymerase at discrete nuclear sites (known as transcription factories), rather than RNA polymerase sliding along DNA template. Based on this transcription factory model, we build a virtual space in which genes and transcription factors move randomly while transcription factories are immobile. We find that under a large number of parameter ranges, this simple dynamical model is valid for a number of experimental observations. Moreover, we suggest the occurrence of gene co-localization might be mainly due to limited numbers of transcription factors, rather than other factors such as nucleus size or transcription factory number. This work offers insight into the general principles of regulation of transcription and gene expression by simulating the translocation of transcriptional units (genes and transcription factors) using purely random diffusion processes that result in non-random organization of co-regulated genes.