Intrinsic dynamics of an endogenous human gene reveal the basis of expression heterogeneity

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. The relationship between these two phenomena and the dynamic regulation of genes in response to upstream signals is unknown. Here, we describe the use of live-cell RNA imaging coupled with Hi-C 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 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. We used 3e HiC to look at the estradiol induced entropy changes for ER bound enhancers.