A multicolour polymer model for the prediction of 3D structure and transcription in human chromatin

Abstract

Within each human cell, different kinds of RNA polymerases and a panoply of transcription factors bind chromatin to simultaneously determine 3D chromosome structure and transcriptional programme. Experiments show that, in some cases, different proteins segregate to form specialised transcription factories; in others they mix together, binding promiscuously the same chromatin stretch. Here, we use Brownian dynamics simulations to study a polymer model for chromosomes accounting for multiple types ('colours') of chromatin-binding proteins. Our multi-colour model shows the spontaneous emergence of both segregated and mixed clusters of chromatin bound proteins, depending mainly on their size, thereby reconciling the previous experimental observations. Additionally, remarkable small-world networks emerge; in these, positive and negative correlations in activities of transcription units provide simple explanations of why adjacent units in large domains are co-transcribed so often, and how one eQTL (expression quantitative trait locus) can up-regulate some genes and down-regulate others. We also explain how local genome edits induce distant om- nigenic and pangenomic effects, and develop ways to predict activities of all transcription units on human chromosomes. All results point to 1D location being a key determinant of transcription, consistently with the conservation of synteny seen between rapidly-evolving enhancers and their more stable target genes.

Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization

“…Future investigations should aim to further elucidate the biological function(s) of such transcription-dependent micro-compartmentalization. Indeed, colocalization of active genomic regions may enhance the recycling of Pol II or transcription co-factors 102,103 by increasing their local concentrations. Investigating precisely such a “structure-function” coupling between the binding and assembly of transcription-associated components and condensates and the spatial folding of the genome remains an intriguing challenge and would require further developments both at the experimental and modeling levels.…”

Work fluctuations for a confined Brownian particle: the role of initial conditions

“…Coherently with what we find here, we note that in [23] the physical origin of the singularity in the rate function of the stationary, free particle was ascribed to a very energetic initial condition. Similarly, a big jump mechanism causing a particle to roll uphill in the potential was suggested in [32] to explain a singular rate function.…”

“…Arguments were given in [23] to conclude that the presence of a harmonic potential would not modify the rate function for the thermal bath work with respect to the free case. Singular rate functions for trajectory dependent quantities have also been found for Brownian particles in a moving potential [27,28] or in contact with several baths [29], for Brownian particles under the action of an additional Gaussian force [30,31], for single harmonically confined active particles [32] and for active Brownian particles at finite densities [33][34][35][36][37].…”