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王耀来, 刘锋

Transcription apparatus: A dancer on a rope

Wang Yaolai, Liu Feng
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  • 转录机器是响应细胞信号并启动基因转录的分子机器. 它控制着基因在恰当的时间以适当的速率表达, 演奏着生命之曲的底层旋律. 为了揭示转录机器的工作原理, 研究人员从其结构、动力学、信号转导等不同的维度进行探索. 研究进程在跌宕起伏中螺旋式上升, 各大研究领域趋于成熟却也趋于独立. 故此, 本文着眼全局, 扼要介绍真核生物转录机器在多领域的重要进展, 着重呈现看似大相径庭的新发现. 结构研究揭示了转录机器的基本架构, 核心争议在于媒介子(也称中介体复合物)的信号传递方式—“变构效应”抑或“招募导引”. 超级增强子的可能工作机制包括令人遐想的“液相分离”和“精确协作”. “转录钟”研究揭示了转录动力学的基本特征. 转录爆发现象的发现, 带来了转录调控机制的“调频”与“调幅”之争—前者得到了更多的支持. 此外, 本文也概述了转录研究的技术困难和理论模型, 提供了基于系综统计方法的研究策略, 并介绍了转录机器的理想模型. 转录机器在DNA上的运转方式源自进化的长河, 似乎是对物理学定律的完美运用与平衡.
    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.
        通信作者:王耀来,yaolaiwang@jiangnan.edu.cn; 刘锋,fliu@nju.edu.cn
        作者简介:
        王耀来, 江南大学理学院校聘副教授, 理学博士, 毕业于南京大学物理学院. 主要从事物理学、数学与生命科学的交叉课题研究与教学. 研究兴趣在于细胞与分子生物学的基础性问题, 目前主要研究转录机器的结构、功能、运转动力学及其信号转导机制. 论文发表在Biol. Rev., Nucleic Acids Res.,Biology等期刊上
        刘锋, 南京大学物理学院教授. 1998年于南京大学获得理学博士学位. 1999年至今一直在南京大学物理系(学院)工作. 从事理论生物物理的研究, 探究基因表达、细胞信号转导和认知行为的动力学及其调控机制, 当前主要研究基因转录爆发、p53信号转导网络、空间导航的神经环路机制等. 论文发表在Sci. Adv., PNAS, J. Neurosci.Phys. Rev. Lett.等期刊上
      • 基金项目:国家自然科学基金(批准号: 11804123, 11831015, 11874209)资助的课题
        Corresponding author:Wang Yaolai,yaolaiwang@jiangnan.edu.cn; Liu Feng,fliu@nju.edu.cn
      • Funds:Project supported by the National Natural Science Foundation of China (Grant Nos. 11804123, 11831015, 11874209)
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    出版历程
    • 收稿日期:2020-09-30
    • 修回日期:2020-11-11
    • 上网日期:2020-12-08
    • 刊出日期:2020-12-20

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