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Intrinsic Dynamics of an Endogenous Human Gene Reveal the Basis of Expression Heterogeneity

71 Pages Posted: 7 Jan 2019 Publication Status: Published

See all articles by Joseph Rodriguez

Joseph Rodriguez

Government of the United States of America - Laboratory of Receptor Biology and Gene Expression

Christopher Day

Government of the United States of America - Laboratory of Biological Modeling

Carson C. Chow

Government of the United States of America - Laboratory of Biological Modeling

Daniel R. Larson

National Institutes of Health - Laboratory of Receptor Biology and Gene Expression

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Abstract

Transcriptional regulation in metazoans occurs through long range genomic contacts between enhancers and promoters, and most genes are transcribed at irregular intervals in episodic 'bursts' of RNA synthesis. The relationship between these two phenomena and the dynamic regulation of genes in human cells in response to upstream signals is unknown. Here, we describe the use of single-molecule live-cell RNA imaging to dissect the regulation of the estrogen-responsive TFF1 gene under endogenous regulation. 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. Surprisingly, alleles are not independent but rather show correlated dynamics in the same nucleus, leading to a regime of 'coupled intrinsic noise'. We derive a mathematical model of regulation which relates the frequency and stability of gene loops to the ability of a cell to 'sense' changes in estrogen.

Suggested Citation

Rodriguez, Joseph and Day, Christopher and Chow, Carson C. and Larson, Daniel R., Intrinsic Dynamics of an Endogenous Human Gene Reveal the Basis of Expression Heterogeneity (2018). Available at SSRN: https://ssrn.com/abstract=3155852 or http://dx.doi.org/10.2139/ssrn.3155852
This version of the paper has not been formally peer reviewed.

Joseph Rodriguez (Contact Author)

Government of the United States of America - Laboratory of Receptor Biology and Gene Expression

National Cancer Institute
Building 41, Room B-602
Bethesda, MD 20892-5055
United States

Christopher Day

Government of the United States of America - Laboratory of Biological Modeling

Bethesda, MD 20892
United States

Carson C. Chow

Government of the United States of America - Laboratory of Biological Modeling ( email )

Bethesda, MD 20892
United States

Daniel R. Larson

National Institutes of Health - Laboratory of Receptor Biology and Gene Expression ( email )

National Cancer Institute
Building 41, Room B-602
Bethesda, MD 20892-5055
United States