Gene structure heterogeneity drives transcription noise within human chromosomes

Abstract

Classical observations have long suggested there is a link between 3D gene structure and transcription. However, due to the many factors regulating gene expression, and to the challenge of visualizing DNA and chromatin dynamics at the same time in living cells, this hypothesis has been difficult to quantitatively test experimentally. Here we take an orthogonal approach and use computer simulations, based on the known biophysical principles of genome organisation, to simultaneously predict 3D structure and transcriptional output of human chromatin genome wide. We validate our model by quantitative comparison with Hi-C contact maps, FISH, GRO-seq and single-cell RNA-seq data, and provide the 3DGene resource to visualise the panoply of structures adopted by any active human gene in a population of cells. We find transcription strongly correlates with the formation of protein-mediated microphase separated clusters of promoters and enhancers, associated with clouds of chromatin loops, and show that gene noise is a consequence of structural heterogeneity. Our results also indicate that loop extrusion by cohesin does not affect average transcriptional patterns, but instead impacts transcriptional noise. These findings provide a functional role for intranuclear microphase separation, and an evolutionary mechanism for loop extrusion halted at CTCF sites, to modulate transcriptional noise.

Chromatin structure from high resolution microscopy: scaling laws and microphase separation

“…This computer model combines several mechanisms of chromosome organization and genomic information. Stochastic simulations from open conformations showed that chromatin forms distinct topologies rather than folding into a single structure [34]. This result is consistent with our findings and the conclusion this paper.…”

Loop stacking organizes genome folding from TADs to chromosomes

“…This would manifest as increased cell-cell variation in mRNA levels, which we observed for most of the developmentally important genes we assayed by single molecule RNA FISH. Recent studies have similarly reported that disruptions in chromatin 3D organization increase variability in gene expression, using single-cell RNA-seq 69 , RNA-FISH and flow-cytometry 70 , or integrative modeling of omics data 71 . Whether and how these acute changes in cell-cell variability due to disruption of chromatin structure connect to functional outcomes of cohesin loss or reduction in development and disease [72][73][74][75][76][77] will require future investigation.…”

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

“…On the one hand, it is widely believed that TADs remain largely invariant in cells with very different transcriptional programs -which points to little role for transcription in determining structure [5] (for an opposing view, see [6]). On the other hand, clusters of active polymerases -called phaseseparated condensates, hubs, and transcription factories [4,[7][8][9][10] -locally stabilise surrounding clouds of loops, thereby providing an example of a structural unit with a clear functional role.…”