Transcriptional Bursting in Gene Expression: Analytical Results for General Stochastic Models

Gene expression in individual cells is highly variable and sporadic, often resulting in the synthesis of mRNAs and proteins in bursts. Such bursting has important consequences for cell-fate decisions in diverse processes ranging from HIV-1 viral infections to stem-cell differentiation. It is generally assumed that bursts are geometrically distributed and that they arrive according to a Poisson process. On the other hand, recent single-cell experiments provide evidence for complex burst arrival processes, highlighting the need for analysis of more general stochastic models. To address this issue, we invoke a mapping between general stochastic models of gene expression and systems studied in queueing theory to derive exact analytical expressions for the moments associated with mRNA/protein steady-state distributions. These results are then used to derive noise signatures, i.e. explicit conditions based entirely on experimentally measurable quantities, that determine if the burst distributions deviate from the geometric distribution or if burst arrival deviates from a Poisson process. For non-Poisson arrivals, we develop approaches for accurate estimation of burst parameters. The proposed approaches can lead to new insights into transcriptional bursting based on measurements of steady-state mRNA/protein distributions.Author Summary: One of the fundamental problems in biology is understanding how phenotypic variations arise among individuals in a population. Recent research has shown that phenotypic variations can arise due to probabilistic cell-fate decisions driven by inherent randomness (noise) in the process of gene expression. One of the manifestations of such stochasticity in gene expression is the production of mRNAs and proteins in bursts. Bursting in gene expression is known to impact cell-fate in diverse systems ranging from latency in HIV-1 viral infections to cellular differentiation. Recent single-cell experiments provide evidence for complex arrival processes leading to bursting, however an analytical framework connecting such burst arrival processes with the corresponding higher moments of mRNA/protein distributions is currently lacking. We address this issue by invoking a mapping between general models of gene expression and systems studied in queueing theory. The framework developed and the results derived lead to new approaches for testing commonly used assumptions in modeling gene expression and for accurate estimation of burst parameters. Notably, the phenomenon of stochastic bursting has been observed in a wide range of disciplines ranging from neuroscience and finance to cell biology. The approaches developed and results obtained in this work will thus contribute towards quantitative characterization of burst processes in diverse systems of current interest.