揭示單細胞訊息系統的非線性特質
Reveal nonlinear properties of signaling systems in single cells
國立臺灣大學海洋所 謝志豪 特聘教授
中央研究院分生所 陳昇宏 助研究員
計畫執行期間：2023.1.1 – 2024.12.31
優良研究成果
During this funding period of 國立臺灣大學與中央研究院創新性合作計畫, we have carried out the following projects and established an international collaboration. Here, we are summarizing these results as an update.
重要成果突破
Project1: Plausible, robust biological oscillations through allelic buffering
Abstract:
Biological oscillators are ubiquitous in nature, orchestrating biological functions in space and time via recurrent activation of their feedback loops. These feedback loops, however, embed multi-step biochemical reactions that naturally generate and amplify biochemical noise. Thus, how biological oscillators, repetitively activating stochastic biochemical reactions, achieve long-term oscillatory dynamics remains unclear. Despite theoretical studies have long explored the evolution of robust oscillators (e.g., PMID: 18599789) as well as the stochastic effects on biological oscillators (e.g., PMID: 37432992), to our knowledge, there is currently no single study directly showcases the occurrence of biochemical noise during biological oscillations; delineates the molecular mechanism underlying robust biological oscillators; and characterizes the phenotypic consequences after crippling the robustness of oscillations. Here, using the oscillations of a cell-fate governor – p53 as an example, we demonstrated that how a robust biological oscillator overcomes biochemical stochasticity by a novel buffering mechanism – allelic buffering, allowing for the precise control of cell fate.
This work is currently under revision in Cell Systems.
Project2: Fine-tuning p53 oscillatory dynamics for cell cycle-specific DNA damage response
Abstract:
Temporal dynamics of signaling molecules can encode biological information that governs physiological homeostasis and stress response. After DNA double strand breaks (DSBs), the tumor suppressor p53 can undergo long-term oscillations for cell cycle arrest. However, cells are not always arrested in all cell cycle phases and can transit between different cell cycle phases after DSBs (e.g., G2 to 4NG1). How does p53 oscillations modulate its oscillatory dynamics to govern cell cycle-specific DNA damage response remains elusive. Using multiplexed p53 reporter cells, we found that p53 oscillator exhibits cell cycle-phase specific oscillatory dynamics. In particular, the p53 oscillator exhibits a more robust oscillatory behavior (i.e., a stronger autocorrelation with a higher amplitude and a shorter period) during G1 and 4NG1 phases compared to those in S and G2 phases. Moreover, p53 oscillator goes through a pronounced dynamic change during G2 to 4NG1 transition. Mathematical modeling of the p53 oscillator indicates possible mechanisms responsible for this distinct oscillatory behavior. We experimentally validated these model-derived predictions and identified the major driving mechanisms for cell cycle-specific p53 dynamics. Finally, we showed that the p53 oscillator is biochemically fined-tuned in order to govern its cell cycle-phase specific functions. Our study showcases cell cycle-specific functions of p53 via modulation of its oscillatory dynamics, and emphasizes the possibility of functional specification via a dedicated regulation of a biological oscillator.
This work is currently under preparation.
國際合作
International collaboration with theoretical physicists: Mathias S Heltberg & Mogens Høgh Jensen in the Niels Bohr Institute, University of Copenhagen, Denmark