Transcription apparatus: A dancer on a rope

Abstract

Laws of physics govern all forms of matter movement. However, lives, which are composed of chemical elements which everyone is familiar with, are largely beyond physical description available. This is because the construction of life is not the same as that of general matters, rendering it unknown how physics laws are utilized. In this paper, we present our thinking on the transcriptional apparatus (TA). The TA is a huge molecular machine acting to sense regulatory signals and initiate transcripts at right time and with right rate. The operation of the TA is fundamental to almost all forms of lives. Although great progress has been made in recent years, one often has to face contradictory conclusions from different studies. Additionally, the studies of transcription are divided into several fields, and different fields are increasingly separate and independent. Focusing on eukaryotic transcription, in this review we briefly describe major advances in various fields and present new conflicting view points. Although the structural studies have revealed the main components and architecture of the TA, it is still unclear how the Mediator complex transmits signals from activators to the core transcriptional machinery at the promoter. It is believed that the Mediator functions to recruit RNA polymerase II onto the promoter and promote the entry into transcriptional elongation, which fails to explain how the signal transduction is achieved. On the other hand, the allostery effect of the Mediator allows for signal transmission but is not supported by structural study. It is reported that enhancers, especially supper enhancers, act to recruit activators via forming a so-called liquid drop and phase separation. By contrast, it is suggested that enhancers should cooperate delicately to orchestrate transcription. Results on the kinetics of protein-promoter interaction also contrast with each other, leading to a paradox called “transcriptional clock”. It is then concluded that proteins interact frequently and transiently with promoters and different proteins interact with the promoter at different stages of transcriptional progression. The phenomenon of transcriptional burst questions how the cellular signaling is achieved through such a noisy manner. While the burst frequency or size, or both are potentially modulated by transcriptional activators, more evidence supports the mode of frequency modulation. The technical difficulties in investigating the mechanism of transcription include 1) structural characterization of flexible and/or unstable proteins or protein complexes, 2) measurement of intermolecular kinetics, 3) tracking of single molecule movement, and 4) lack of methodology in theoretical research. We further propose a research strategy based on the ensemble statistical method, and introduce a model for how the TA dynamically operates. The model may act as a benchmark for further investigations. The operating mechanism of the TA should reflect an optimal use of physics laws as a result of long-term biological evolution.