Bridging-Induced Phase Separation and Loop Extrusion Drive Noise in Chromatin Transcription

Cell-to-cell heterogeneity in transcription, or transcriptional noise, is important in cellular development and in disease. The molecular mechanisms driving it are, however, elusive and ill-understood. Here, we use computer simulations to explore the role of 3D chromatin structure in driving transcriptional noise. We study a simple polymer model where proteins-modeling complexes of transcription factors and polymerases-bind multivalently to transcription units-modeling regulatory elements such as promoters and enhancers. We also include cohesinlike factors that extrude chromatin loops that are important for the physiological folding of chromosomes. We find that transcription factor binding creates spatiotemporal patterning and a highly variable correlation time in transcriptional dynamics, which is linked to the cell-to-cell variation in gene expression. Loop extrusion also contributes to noise, as the stochastic nature of this process leads to different networks of cohesin loops in different cells in our model. Our results could be tested with single-cell experiments and provide a pathway to understanding the principles underlying transcriptional plasticity in vivo.