Effects of the Dynamics of the Steps in Transcription Initiation on the Asymmetry of the Distribution of Time Intervals between Consecutive RNA Productions

Asymmetries in the distribution of time intervals between consecutive RNA pro-ductions from a gene can play a critical role in, e.g., allowing/preventing the RNA and, thus, protein numbers to cross thresholds involved in gene network decision making. Here, we use a stochastic, multi-step model of transcription initiation, with all rate constants empirically validated, and explore how the kinetics of its steps affect the temporal asymmetries in RNA production, as measured by the skewness of the distribution of intervals between consecutive RNA productions in individual cells. From the model, first, we show that this skewness differs widely with the mean fraction of time that the RNA polymerase spends in the steps preceding open complex formation, while being independent of the mean transcription rate. Next, we provide empirical validation of these results, using qPCR and live, time-lapse, single-molecule RNA microscopy measurements of the transcription kinetics of multiple promoters. We conclude that the skewness in RNA production kinetics is subject to regulation by the kinetics of the steps in transcription initiation and, thus, evolvable.