Signaling Mechanism of Transcriptional Bursting: A Technical Resolution-Independent Study

SIMPLE SUMMARY: Following changing cellular signals, various genes adjust their activities and initiate transcripts with the right rates. The precision of such a transcriptional response has a fundamental role in the survival and development of lives. Quite unexpectedly, gene transcription has been uncovered to occur in sporadic bursts, rather than in a continuous manner. This has raised a provoking issue of how the bursting transmits regulatory signals, and it remains controversial whether the burst size, frequency, or both, take the role of signal transmission. Here, this study showed that only the burst frequency was subject to modulation by activators that carry the regulatory signals. A higher activator concentration led to a larger frequency, whereas the size remains unchanged. When very high, the burst cluster emerged, which may be mistaken as a large burst. This work thus supports the conclusion that transcription regulation is in a “digital” way. ABSTRACT: Gene transcription has been uncovered to occur in sporadic bursts. However, due to technical difficulties in differentiating individual transcription initiation events, it remains debated as to whether the burst size, frequency, or both are subject to modulation by transcriptional activators. Here, to bypass technical constraints, we addressed this issue by introducing two independent theoretical methods including analytical research based on the classic two-model and information entropy research based on the architecture of transcription apparatus. Both methods connect the signaling mechanism of transcriptional bursting to the characteristics of transcriptional uncertainty (i.e., the differences in transcriptional levels of the same genes that are equally activated). By comparing the theoretical predictions with abundant experimental data collected from published papers, the results exclusively support frequency modulation. To further validate this conclusion, we showed that the data that appeared to support size modulation essentially supported frequency modulation taking into account the existence of burst clusters. This work provides a unified scheme that reconciles the debate on burst signaling.