Dynamic barriers modulate cohesin positioning and genome folding at fixed occupancy.

Area of Science:

• Genomics
• Molecular Biology
• Biophysics

Background:

• Mammalian genome folding in interphase cells involves cohesin loop extrusion constrained by directional CTCF binding.
• Topologically associating domains (TADs) are formed and maintained by this process, with cohesin enrichment at CTCF sites.
• A discrepancy exists between short CTCF residence times and longer cohesin lifetimes, posing a question about barrier dynamics.

Purpose of the Study:

• To investigate if transient CTCF barriers can explain observed genome folding patterns.
• To develop a dynamic barrier model incorporating CTCF binding and unbinding.
• To assess the impact of barrier dynamics on genomic and imaging data.

Main Methods:

• Developed a dynamic barrier model where CTCF sites switch between bound and unbound states.
• Simulated ChIP-seq, Hi-C, and microscopy data using the dynamic barrier model.
• Integrated multiple experimental data sources to validate the model.

Main Results:

• Found that CTCF and cohesin binding timescales significantly influence genome folding features.
• Demonstrated that barrier bound times, not just occupancy, are critical for genome structure.
• Showed that the ratio of boundary to extruder lifetime impacts simulated ChIP-seq and Hi-C data.
• Observed that dynamic barriers are necessary to explain experimental changes in chromosome morphology.

Conclusions:

• CTCF barrier dynamics are essential for understanding genome folding, even with transient barriers.
• The model suggests that CTCF barrier bound times are comparable to cohesin extruder lifetimes.
• Biophysically informed models of protein dynamics enhance our comprehension of genome folding mechanisms.