Intrinsic Dynamics of an Endogenous Human Gene Reveal the
Basis of Information Transfer in Expression Regulation
Laboratory of Receptor Biology and Gene Expression
National Institutes of Health
Wed, October 24, 2018 - 4:00 PM
Karl Herzfeld Auditorium of Hannan Hall - Rm 108
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 coupled with genome-wide chromosome conformation measurements to dissect the regulation of the estrogen-responsive TFF1 gene under endogenous regulation. Although this gene 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 intact human tissue. Surprisingly, alleles are not independent but rather show correlated dynamics in the same nucleus, leading to a regime of ‘coupled intrinsic noise’ which dominates expression variability. We derive a mathematical model of regulation which relates transcription, chromosome structure, and the ability of a cell to ‘sense’ changes in estrogen and predicts that hypervariability is largely dynamic and does not reflect a stable biological state.
Refreshments served at 3:45 PM
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