Dynamical mRNA distribution regulated by multi-step gene activation

Transcriptional bursting has been attributed to the random switch between the off and on states of genes. Previous studies modeled gene activation as a process involving ordered multiple rate-limiting steps. Here, we aimed to understand how multi-step gene activation regulates the dynamical mRNA distribution in isogenic cell populations. We focused on both inactive and active genes for which the gene shows a longer average duration in the off and on states, respectively. We developed a method to calculate the mRNA distribution and demonstrated the unstable dynamical bimodal distribution induced by multi-step activation. The suppression of bimodality requires only a few activation steps and is achieved by triggering more cells to express the gene. In the gene-expressing cell population, multi-step gene activation modulates the transcription distribution in a bidirectional manner: the inactive gene is transcribed with enhanced heterogeneity, whereas the active gene is facilitated to generate homogeneous transcription dynamics. These regulation scenarios guide the understanding of the network structure of signaling pathways that direct gene activation.