Modulating gene regulation function by chemically controlled transcription factor clustering

被引:20
作者
Wu, Jiegen [1 ,2 ,3 ,4 ]
Chen, Baoqiang [4 ]
Liu, Yadi [1 ,2 ,3 ]
Ma, Liang [1 ,2 ,3 ]
Huang, Wen [1 ,2 ,3 ]
Lin, Yihan [1 ,2 ,3 ]
机构
[1] Peking Univ, Acad Adv Interdisciplinary Studies, Ctr Quantitat Biol, Beijing 100871, Peoples R China
[2] Peking Univ, Sch Life Sci, MOE Key Lab Cell Proliferat & Differentiat, Beijing 100871, Peoples R China
[3] Peking Univ, Acad Adv Interdisciplinary Studies, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China
[4] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
SYNTHETIC BIOLOGY; PHASE-SEPARATION; DYNAMICS; COMBINATORIAL; INDUCTION; CELLS; MAP;
D O I
10.1038/s41467-022-30397-2
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Recent studies have suggested that transcriptional protein condensates (or clusters) may play key roles in gene regulation and cell fate determination. However, it remains largely unclear how the gene regulation function is quantitatively tuned by transcription factor (TF) clustering and whether TF clustering may confer emergent behaviors as in cell fate control systems. Here, to address this, we construct synthetic TFs whose clustering behavior can be chemically controlled. Through single-parameter tuning of the system (i.e., TF clustering propensity), we provide lines of evidence supporting the direct transcriptional activation and amplification of target genes by TF clustering. Single-gene imaging suggests that such amplification results from the modulation of transcriptional dynamics. Importantly, TF clustering propensity modulates the gene regulation function by significantly tuning the effective TF binding affinity and to a lesser extent the ultrasensitivity, contributing to bimodality and sustained response behavior that are reminiscent of canonical cell fate control systems. Collectively, these results demonstrate that TF clustering can modulate the gene regulation function to enable emergent behaviors, and highlight the potential applications of chemically controlled protein clustering. Transcription factor (TF) condensates appear to be pervasive, yet their roles remain debated. Here, the authors use a synthetic biology approach to show that TF clusters causally amplify transcription and can confer bimodality and "memory".
引用
收藏
页数:15
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