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

TL;DR

This study uses computer simulations of chromatin structure to reveal how phase separation and loop extrusion contribute to transcriptional noise, highlighting mechanisms of intrinsic and extrinsic variability in gene expression.

Contribution

It introduces a polymer model incorporating multivalent protein binding and loop extrusion to explain sources of transcriptional noise in chromatin.

Findings

Protein binding causes variable transcriptional dynamics.

Loop extrusion leads to cell-to-cell variability in chromatin structure.

Simulation results suggest mechanisms for transcriptional plasticity.

Abstract

Transcriptional noise, or heterogeneity, 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 cohesin-like factors which 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, providing a mechanism for intrinsic noise within a single cell. Instead, loop extrusion contributes to extrinsic noise, as the stochastic nature of this process leads to different networks of cohesin loops in different cells in our simulations. Our results could be tested with single-cell experiments and provide a pathway to understanding the principles underlying transcriptional plasticity in vivo.