Cohesin and CTCF complexes mediate contacts in chromatin loops depending on nucleosome positions

Area of Science:

• Genomics
• Molecular Biology
• Biophysics

Background:

• The spatial organization of eukaryotic genomes, particularly chromatin looping, is vital for regulating gene expression.
• Topologically associating domains (TADs) are fundamental units of genome organization, formed by chromatin loops stabilized by cohesin and CCCTC-binding factor (CTCF).
• Current high-resolution conformation capture techniques face limitations in throughput, resolution, and data noise, hindering the identification of intra-loop contacts.

Purpose of the Study:

• To investigate the impact of cohesin and CTCF on chromatin loop formation and internal structure.
• To explore how nucleosome positioning and loop size influence contact frequency and organization within chromatin loops.
• To understand the role of nucleosome distribution in the formation of microloops within larger cohesin-mediated loops.

Main Methods:

• Extension of a coarse-grained chromatin model to include potentials for CTCF and cohesin.
• Replica-exchange Monte Carlo simulations were performed using both regular and experimentally determined nucleosome positions.
• Simulations included control systems with depleted cohesin and CTCF to assess their specific contributions.

Main Results:

• The presence of cohesin and CTCF significantly increased contact frequency within extruded chromatin loops.
• Nucleosome distribution and loop size were found to modulate the number and types of intra-loop contacts.
• Microloops formed within cohesin-mediated loops due to thermal fluctuations, with their characteristics dependent on nucleosome distribution and loop size.

Conclusions:

• Nucleosome positioning is a critical determinant of spatial structure and contact probability within chromatin loops.
• These findings suggest that nucleosome arrangement directly influences transcriptional regulation through modulation of genome organization.
• The study provides a refined model for understanding the physical basis of chromatin loop function in gene regulation.