Live imaging and biophysical modeling support a button-based mechanism of somatic homolog pairing in Drosophila
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Curated by eLife
Evaluation Summary:
This manuscript considers an important open problem in molecular biology, that is how distal chromosomes can recognise each other at a distance and become paired, as happens for example in homolog paring in Drosophila. To address this question, the authors combine theoretical models and experiments, which return valuable insights. However, a final proof of the envisaged mechanisms remains to be determined.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Three-dimensional eukaryotic genome organization provides the structural basis for gene regulation. In Drosophila melanogaster , genome folding is characterized by somatic homolog pairing, where homologous chromosomes are intimately paired from end to end; however, how homologs identify one another and pair has remained mysterious. Recently, this process has been proposed to be driven by specifically interacting ‘buttons’ encoded along chromosomes. Here, we turned this hypothesis into a quantitative biophysical model to demonstrate that a button-based mechanism can lead to chromosome-wide pairing. We tested our model using live-imaging measurements of chromosomal loci tagged with the MS2 and PP7 nascent RNA labeling systems. We show solid agreement between model predictions and experiments in the pairing dynamics of individual homologous loci. Our results strongly support a button-based mechanism of somatic homolog pairing in Drosophila and provide a theoretical framework for revealing the molecular identity and regulation of buttons.
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Joint Public Review:
The way homologous chromosomes identify one another and become paired is an intriguing phenomenon that has a long history of study, yet the molecular mechanism remains unclear. Recent studies have led to a phenomenological button model for homolog pairing, which hypothesizes that pairing is initiated at discrete sites along the length of each chromosome. The authors aimed to rigorously investigate this idea using biophysical modeling and live imaging. They first constructed a simple polymer model with buttons distributed along the chain that possess locus-specific interactions, and thoroughly investigated its property via stochastic simulation in 3D. Their study confirms that homolog-specific interactions are necessary for homolog pairing. They also tested the effect of time, interaction strength, initial …
Joint Public Review:
The way homologous chromosomes identify one another and become paired is an intriguing phenomenon that has a long history of study, yet the molecular mechanism remains unclear. Recent studies have led to a phenomenological button model for homolog pairing, which hypothesizes that pairing is initiated at discrete sites along the length of each chromosome. The authors aimed to rigorously investigate this idea using biophysical modeling and live imaging. They first constructed a simple polymer model with buttons distributed along the chain that possess locus-specific interactions, and thoroughly investigated its property via stochastic simulation in 3D. Their study confirms that homolog-specific interactions are necessary for homolog pairing. They also tested the effect of time, interaction strength, initial inter-homolog distance, and button density. The authors went on to perform live imaging of pairing dynamics at two selected loci, using the fluorescent signal from nascent mRNA at the corresponding locus. They fitted the model to the experimentally quantified pairing probability of the selected loci over a 6-hour developmental window, and used the constrained model to predict the individual pairing dynamics. The predicted inter-homolog distance post pairing agrees very well with experimental observation.
Their study supports a button mechanism for homolog pairing, where stable pairing is initiated by reversible random encounters that are propagated chromosome-wide. This work suggests that active processes are not necessary to explain pairing and paves the way for further investigating the molecular mechanism of such a pairing phenomenon.
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Evaluation Summary:
This manuscript considers an important open problem in molecular biology, that is how distal chromosomes can recognise each other at a distance and become paired, as happens for example in homolog paring in Drosophila. To address this question, the authors combine theoretical models and experiments, which return valuable insights. However, a final proof of the envisaged mechanisms remains to be determined.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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