Dynamic Imaging of Nascent RNA Reveals General Principles of Transcription Dynamics

The stochastic activities of RNA polymerase and the spliceosome are responsible for the heterogeneity of the abundance and isoform composition of mRNA in human cells. However, the dynamics of these megadalton enzymatic complexes working in concert on endogenous genes have not been described. Here, we establish a quasi-genome-scale platform for observing synthesis and processing kinetics of single nascent RNA molecules in real time. We find that all observed genes show transcriptional bursting. 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 upstream signals and predicts that hypervariability is largely dynamic and does not reflect a stable biological state.