Bridging-Induced Phase Separation and Loop Extrusion Drive Noise in Chromatin Transcription.

Area of Science:

• Molecular Biology
• Genomics
• Computational Biology

Background:

• Cell-to-cell heterogeneity in transcription, known as transcriptional noise, plays a crucial role in cellular development and disease.
• The underlying molecular mechanisms driving transcriptional noise remain poorly understood.

Purpose of the Study:

• To investigate the role of three-dimensional (3D) chromatin structure in generating transcriptional noise using computational simulations.
• To elucidate the molecular mechanisms by which chromatin organization influences gene expression variability.

Main Methods:

• Development of a polymer model simulating transcription units (promoters, enhancers) and protein complexes (transcription factors, polymerases).
• Inclusion of cohesin-like factors to model chromatin loop extrusion, crucial for chromosome folding.
• Analysis of spatiotemporal dynamics and correlation times of transcriptional activity.

Main Results:

• Transcription factor binding was found to induce spatiotemporal patterning and variable correlation times in transcriptional dynamics.
• This variability in dynamics directly correlates with observed cell-to-cell variation in gene expression.
• Stochastic loop extrusion by cohesin-like factors also contributes to transcriptional noise by creating diverse chromatin loop networks.

Conclusions:

• 3D chromatin structure, through transcription factor interactions and loop extrusion, is a significant driver of transcriptional noise.
• The findings provide a mechanistic framework for understanding transcriptional plasticity in vivo.
• The results are testable via single-cell experimental approaches.