Fluctuating Chromatin Facilitates Enhancer-Promoter Communication by Regulating Transcriptional Clustering Dynamics

Area of Science:

• Molecular Biology
• Biophysics
• Genetics

Background:

• Enhancers regulate gene expression by interacting with distant promoters.
• Transcription factor (TF) clusters and phase-separated condensates are hypothesized to mediate these enhancer-promoter (E-P) interactions.

Purpose of the Study:

• To investigate the physical mechanisms underlying enhancer-promoter communication.
• To develop and analyze chromatin models that capture distinct dynamic properties.

Main Methods:

• Utilized polymer physics to create distinct coarse-grained chromatin models.
• Compared ensemble-averaged Hi-C maps from stable and dynamic models.
• Analyzed the role of TF clustering and chromatin flexibility in E-P interactions.

Main Results:

• Developed models yielding similar Hi-C maps but differing in stability and dynamics.
• Identified a multistep E-P communication process.
• Demonstrated that dynamic models enhance TF clustering for proximity and then destabilize clusters via chain flexibility to promote direct E-P interactions.

Conclusions:

• The physical properties of chromatin, particularly chain flexibility, are crucial for E-P communication.
• TF cluster dynamics play a key role in facilitating and stabilizing E-P interactions.
• This work provides a physical understanding of transcriptional regulation mechanisms.