Modulating gene regulation function by chemically controlled transcription factor clustering

Area of Science:

• Molecular Biology
• Biophysics
• Systems Biology

Background:

• Protein condensates, including transcriptional protein clusters, are implicated in gene regulation and cell fate determination.
• Quantitative understanding of how transcription factor (TF) clustering influences gene regulation and confers emergent properties is limited.

Purpose of the Study:

• To investigate the quantitative relationship between TF clustering and gene regulation.
• To determine if TF clustering can lead to emergent behaviors analogous to cell fate control systems.

Main Methods:

• Construction of synthetic TFs with chemically controllable clustering behavior.
• Single-parameter tuning of TF clustering propensity.
• Single-gene imaging to analyze transcriptional dynamics.

Main Results:

• TF clustering directly activates and amplifies target gene expression.
• Amplification arises from the modulation of transcriptional dynamics.
• Clustering propensity tunes TF binding affinity and ultrasensitivity, leading to bimodality and sustained responses.

Conclusions:

• TF clustering is a key mechanism for modulating gene regulation and enabling emergent behaviors.
• Chemically controlled protein clustering offers potential applications in synthetic biology and understanding cell fate decisions.