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

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


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.

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

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Estrogen Receptor alpha / metabolism
  • Estrogens
  • Gene Expression / genetics
  • Gene Expression / physiology*
  • Gene Expression Regulation / physiology*
  • Humans
  • Models, Theoretical
  • Promoter Regions, Genetic / physiology
  • RNA, Messenger / metabolism
  • Single-Cell Analysis / methods
  • Transcription, Genetic / genetics
  • Transcription, Genetic / physiology*
  • Transcriptional Activation / physiology
  • Trefoil Factor-1 / genetics


  • Estrogen Receptor alpha
  • Estrogens
  • RNA, Messenger
  • TFF1 protein, human
  • Trefoil Factor-1