Regulation of chromatin transcription via DNA supercoiling

Transcription is a mechanical process wherein the translocation of the transcription machinery or RNA polymerase (RNAP) on DNA or chromatin is dynamically coupled to the chromatin mechanics. This posits chromatin mechanics as a possible regulator of eukaryotic transcription, however, the modes and mechanisms of this regulation are elusive. Here, we first take a statistical mechanics approach to model the mechanical response of a topology-constrained chromatin fiber to twisting perturbations. Our model recapitulates the experimentally observed weaker torsional response of chromatin compared to bare DNA, and proposes structural transitions of nucleosomes into chirally distinct states as the driver of the contrasting torsional mechanics. Coupling chromatin mechanics with RNAP translocation in stochastic simulations, we reveal a complex interplay of DNA supercoiling and nucleosome dynamics in governing RNAP velocity. Nucleosomes play a dual role in controlling the transcription dynamics. The steric barrier aspect of nucleosomes counteracts transcription via hindering RNAP motion, whereas, the chiral transitions via driving a low restoring torque upon twisting the DNA facilitate RNAP motion. While low rates of nucleosome dissociation from DNA are typically transcriptionally repressive, highly dynamic nucleosomes offer less steric barrier and enhance the transcription dynamics of weakly transcribed genes via screening DNA twist. We use the model to predict transcription-dependent levels of DNA supercoiling in segments of the budding yeast genome that are in quantitative accord with available experimental data. The model unveils a paradigm of DNA supercoiling-mediated interaction between genes and makes testable predictions that will guide experimental design.