Nonequilibrium Biophysical Processes Influence the Large-Scale Architecture of the Cell Nucleus

Model approaches to nuclear architecture have traditionally ignored the biophysical consequences of ATP-fueled active processes acting on chromatin. However, transcription-coupled activity is a source of stochastic forces that are substantially larger than the Brownian forces present at physiological temperatures. Here, we describe an approach to large-scale nuclear architecture in metazoans that incorporates cell-type-specific active processes. The model predicts the statistics of positional distributions, shapes, and overlaps of each chromosome. Simulations of the model reproduce common organizing principles underlying large-scale nuclear architecture across human cell nuclei in interphase. These include the differential positioning of euchromatin and heterochromatin, the territorial organization of chromosomes (including both gene-density-based and size-based chromosome radial positioning schemes), the nonrandom locations of chromosome territories, and the shape statistics of individual chromosomes. We propose that the biophysical consequences of the distribution of transcriptional activity across chromosomes should be central to any chromosome positioning code.