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

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.