Stochastic motion and transcriptional dynamics of pairs of distal DNA loci on a compacted chromosome

July 03, 2023 | Author: Thomas Gregor | Posted in Publications

David B. Brückner, Hongtao Chen, Lev Barinov, Benjamin Zoller, Thomas Gregor. Science 380, 1357-1362 (2023).

Microscopy image of nuclei in a living fly embryo visualizing the relationship between DNA topology and gene activity. It shows how two specific pieces of DNA, called enhancer (blue) and promoter (green), need to be in physical proximity for gene activity (red) to occur. Following the motion of these elements linked by the DNA string in real time reveals that DNA is densely packed, and therefore close together – yet exhibit fast motion allowing the elements to come into contact quickly. (Created by D Brückner)

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Abstract

Chromosomes in the eukaryotic nucleus are highly compacted. However, for many functional processes, including transcription initiation, the pairwise motion of distal chromosomal elements such as enhancers and promoters is essential and necessitates dynamic fluidity. Here, we used a live-imaging assay to simultaneously measure the positions of pairs of enhancers and promoters and their transcriptional output while systematically varying the genomic separation between these two DNA loci. Our analysis reveals the coexistence of a compact globular organization and fast subdiffusive dynamics. These combined features cause an anomalous scaling of polymer relaxation times with genomic separation leading to long-ranged correlations. Thus, encounter times of DNA loci are much less dependent on genomic distance than predicted by existing polymer models, with potential consequences for eukaryotic gene expression.

Video shows how physical proximity between two specific pieces of DNA, called enhancer and promoter, is necessary for gene activity. Three cell nuclei are labeled with numbers. The target gene is not activated in nucleus 1 or 2. In these two nuclei, a clear physical separation between the enhancer (blue spot) and the gene (green spot) is observed. In nucleus 3 where the target gene is active (red spot), the blue and green spots overlap. (Created by H Chen)

Editor’s Summary

A crucial step in gene regulation is the physical encounter of dispersed enhancer-promoter pairs across the genome. However, how distal DNA elements find each other in the nuclear space remains unclear. Brückner et al. visualized the three-dimensional motion of pairs of DNA loci of varying separations along the chromosome and their transcriptional output in developing fly embryos. They found an unexpected combination of dense packing and rapid diffusion, leading to encounter times with a weak dependence on genomic separation. These results imply that transcriptional contacts are possible across large genomic distances, with crucial implications for gene regulation.
—Di Jiang (Science Magazine)

David’s summary on Twitter

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