Transient crosslinking kinetics optimize gene cluster interactions

Our understanding of how chromosomes structurally organize and dynamically interact has been revolutionized through the lens of long-chain polymer physics. Major protein contributors to chromosome structure and dynamics are condensin and cohesin that stochastically generate loops within and between...

Full description

Saved in:
Bibliographic Details
Published in:PLoS computational biology 2019-08, Vol.15 (8), p.e1007124-e1007124
Main Authors: Walker, Benjamin, Taylor, Dane, Lawrimore, Josh, Hult, Caitlin, Adalsteinsson, David, Bloom, Kerry, Forest, M Gregory
Format: Article
Language:English
Subjects:
Algorithms
Analysis
Architectural engineering
Biology
Biology and Life Sciences
Cell Nucleolus - genetics
Chain dynamics
Chemical kinetics
Chromatids
Chromosomes
Clustering
Cohesin
Computational Biology
Computer and Information Sciences
Computer applications
Computer Simulation
Condensin
Cross-Linking Reagents
Crosslinking
Data analysis
Databases, Genetic
Datasets
Deoxyribonucleic acid
DNA
Domains
Gene clusters
Gene expression
Genes
Genome, Fungal
Genomes
Hox genes
Image analysis
Image processing
Kinetics
Mathematics
Methods
Microscopy
Models, Genetic
Multigene Family
Mutation
Nucleoli
Optimization
Physical Sciences
Polymer physics
Polymers
Protein crosslinking
Protein structure
Proteins
Research and Analysis Methods
Ribosomal DNA
Saccharomyces cerevisiae - cytology
Saccharomyces cerevisiae - genetics
Sister chromatids
Software
Spatio-Temporal Analysis
Yeast
Yeasts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Our understanding of how chromosomes structurally organize and dynamically interact has been revolutionized through the lens of long-chain polymer physics. Major protein contributors to chromosome structure and dynamics are condensin and cohesin that stochastically generate loops within and between chains, and entrap proximal strands of sister chromatids. In this paper, we explore the ability of transient, protein-mediated, gene-gene crosslinks to induce clusters of genes, thereby dynamic architecture, within the highly repeated ribosomal DNA that comprises the nucleolus of budding yeast. We implement three approaches: live cell microscopy; computational modeling of the full genome during G1 in budding yeast, exploring four decades of timescales for transient crosslinks between 5kbp domains (genes) in the nucleolus on Chromosome XII; and, temporal network models with automated community (cluster) detection algorithms applied to the full range of 4D modeling datasets. The data analysis tools detect and track gene clusters, their size, number, persistence time, and their plasticity (deformation). Of biological significance, our analysis reveals an optimal mean crosslink lifetime that promotes pairwise and cluster gene interactions through "flexible" clustering. In this state, large gene clusters self-assemble yet frequently interact (merge and separate), marked by gene exchanges between clusters, which in turn maximizes global gene interactions in the nucleolus. This regime stands between two limiting cases each with far less global gene interactions: with shorter crosslink lifetimes, "rigid" clustering emerges with clusters that interact infrequently; with longer crosslink lifetimes, there is a dissolution of clusters. These observations are compared with imaging experiments on a normal yeast strain and two condensin-modified mutant cell strains. We apply the same image analysis pipeline to the experimental and simulated datasets, providing support for the modeling predictions.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1007124