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Cell. 2019 Jan 10;176(1-2):213-226.e18. doi: 10.1016/j.cell.2018.11.026. Epub 2018 Dec 13.

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

Author information

1
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA.
2
Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Behesda, MD, USA.
3
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA. Electronic address: carson.chow@nih.gov.
4
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: dan.larson@nih.gov.

Abstract

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 useĀ 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.

KEYWORDS:

RNA; chromosome; estrogen; fluorescence; heterogeneity; imaging; live-cell; single-molecule; steroid; transcription

PMID:
30554876
PMCID:
PMC6331006
[Available on 2020-01-10]
DOI:
10.1016/j.cell.2018.11.026

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