Modelling transcriptional silencing and its coupling to 3D genome organisation

TL;DR

This paper uses 3D simulations to explore how different gene silencing mechanisms influence chromatin structure, transcription activity, and gene regulation, revealing distinct structural and functional signatures for each silencing pathway.

Contribution

It introduces a biophysical model of gene silencing that links feedback mechanisms to 3D genome organization and transcriptional outcomes.

Findings

All silencing mechanisms induce a transition to silenced states.

Silencing feedback type affects 3D chromatin morphology and gene expression variability.

Different mechanisms produce distinct patterns of transcription factor clustering and gene activity correlations.

Abstract

Timely up- or down-regulation of gene expression is crucial for cellular differentiation and function. While gene upregulation via transcriptional activators has been extensively investigated, gene silencing remains understudied, especially by modelling. This study employs 3D simulations to study the biophysics of a chromatin fibre where active transcription factors compete with repressors for binding to transcription units along the fibre, and investigates how different silencing mechanisms affect 3D chromatin structure and transcription. We examine three gene silencing feedback mechanisms: positive, negative, and neutral. These mechanisms capture different silencing pathways observed or proposed in biological systems. Our findings reveal that, whilst all mechanisms lead to a silencing transition, the signatures of this transition depend on the choice of the feedback. The latter controls the morphologies of the emergent 3D transcription factor clusters, the average gene expression and its variability, or gene noise, and the network of ensuing correlations between activities of neighbouring transcription units. These results provide insights into the biophysics of gene silencing, as well as into the interplay between transcriptional regulation and 3D genome organisation.