Intrinsic Dynamics of a Human Gene Reveal the Basis of Expression Heterogeneity

Transcriptional regulation in metazoans occurs through long-range genomic contacts between enhancers and promoters, and most genes are transcribed in episodic “bursts” of RNA synthesis. To understand the relationship between these two phenomena and the dynamic regulation of genes in response to upst...

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Bibliographic Details
Published in:Cell 2019-01, Vol.176 (1-2), p.213-226.e18
Main Authors: Rodriguez, Joseph, Ren, Gang, Day, Christopher R., Zhao, Keji, Chow, Carson C., Larson, Daniel R.
Format: Article
Language:English
Subjects:
chromosome
estrogen
Estrogen Receptor alpha - metabolism
Estrogens
fluorescence
Gene Expression - genetics
Gene Expression - physiology
Gene Expression Regulation - physiology
heterogeneity
Humans
imaging
live-cell
Models, Theoretical
Promoter Regions, Genetic - physiology
RNA
RNA, Messenger - metabolism
Single-Cell Analysis - methods
single-molecule
steroid
transcription
Transcription, Genetic - genetics
Transcription, Genetic - physiology
Transcriptional Activation - physiology
Trefoil Factor-1 - genetics
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Summary:Transcriptional regulation in metazoans occurs through long-range genomic contacts between enhancers and promoters, and most genes are transcribed in episodic “bursts” of RNA synthesis. To understand the relationship between these two phenomena and the dynamic regulation of genes in response to upstream signals, we describe the use of live-cell RNA imaging coupled with Hi-C measurements and dissect the endogenous regulation of the estrogen-responsive TFF1 gene. Although TFF1 is highly induced, we observe short active periods and variable inactive periods ranging from minutes to days. The heterogeneity in inactive times gives rise to the widely observed “noise” in human gene expression and explains the distribution of protein levels in human tissue. We derive a mathematical model of regulation that relates transcription, chromosome structure, and the cell’s ability to sense changes in estrogen and predicts that hypervariability is largely dynamic and does not reflect a stable biological state. [Display omitted] •Live-cell RNA imaging reveals that long repressive states cause expression variability•Highly variable expression occurs in functional gene ontology categories•Alleles are not independent•Information theory explains how estrogen is sensed by the cell Time-dependent dynamics of promoter-enhancer associations contribute to transcriptional noise and shape responses to ligand-dependent gene induction.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2018.11.026