Synthetic analysis of chromatin tracing and live-cell imaging indicates pervasive spatial coupling between genes

Abstract
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Abstract

The role of the spatial organization of chromosomes in directing transcription remains an outstanding question in gene regulation. Here, we analyze two recent single-cell imaging methodologies applied across hundreds of genes to systematically analyze the contribution of chromosome conformation to transcriptional regulation. Those methodologies are: 1) single-cell chromatin tracing with super-resolution imaging in fixed cells; 2) high throughput labeling and imaging of nascent RNA in living cells. Specifically, we determine the contribution of physical distance to the coordination of transcriptional bursts. We find that individual genes adopt a constrained conformation and reposition toward the centroid of the surrounding chromatin upon activation. Leveraging the variability in distance inherent in single-cell imaging, we show that physical distance - but not genomic distance - between genes on individual chromosomes is the major factor driving co-bursting. By combining this analysis with live-cell imaging, we arrive at a corrected transcriptional correlation of ϕ ≈0.3 for genes separated by < 400 nm. We propose that this surprisingly large correlation represents a physical property of human chromosomes and establishes a benchmark for future experimental studies.

Data availability

The current manuscript is a computational study. Analysis code and modeling code are included in GitHub. https://github.com/CHB-Bohrer/co-bursting

The following previously published data sets were used

(2020) chromosome21.tsv
zenodo.

https://zenodo.org/record/3928890#.YuAs2-zMJhE

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Author details

Christopher H Bohrer

Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Daniel R Larson

Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, Bethesda, United States

For correspondence
dan.larson@nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9253-3055

Funding

National Institutes of Health

Christopher H Bohrer

National Institutes of Health

Daniel R Larson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.