Polymer perspective of genome mobilization

Lawrimore, Colleen J.; Lawrimore, Josh; He, Yunyan; Chávez, Sergio Jorge; Bloom, Kerry

doi:10.1016/j.mrfmmm.2020.111706

Cited by 5 publications

(4 citation statements)

References 152 publications

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“…2 D , chromatin diffusion at DSBs was significantly higher than in undamaged regions. These measurements reconcile our observations with the well-established acceleration of damage sites in yeasts ( 1 ). As an independent approach to assess global chromatin motions in response to DNA damage, DNA replication foci were labeled by the incorporation of fluorescent nucleotides (CF488-dUTP) ( 28 ) and tracked using confocal microscopy ( SI Appendix , Fig.…”

Section: Resultssupporting

confidence: 91%

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DNA damage reduces heterogeneity and coherence of chromatin motions

Locatelli

Lawrimore

Lin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Chromatin motions depend on and may regulate genome functions, in particular the DNA damage response. In yeast, DNA double-strand breaks (DSBs) globally increase chromatin diffusion, whereas in higher eukaryotes the impact of DSBs on chromatin dynamics is more nuanced. We mapped the motions of chromatin microdomains in mammalian cells using diffractive optics and photoactivatable chromatin probes and found a high level of spatial heterogeneity. DNA damage reduces heterogeneity and imposes spatially defined shifts in motions: Distal to DNA breaks, chromatin motions are globally reduced, whereas chromatin retains higher mobility at break sites. These effects are driven by context-dependent changes in chromatin compaction. Photoactivated lattices of chromatin microdomains are ideal to quantify microscale coupling of chromatin motion. We measured correlation distances up to 2 µm in the cell nucleus, spanning chromosome territories, and speculate that this correlation distance between chromatin microdomains corresponds to the physical separation of A and B compartments identified in chromosome conformation capture experiments. After DNA damage, chromatin motions become less correlated, a phenomenon driven by phase separation at DSBs. Our data indicate tight spatial control of chromatin motions after genomic insults, which may facilitate repair at the break sites and prevent deleterious contacts of DSBs, thereby reducing the risk of genomic rearrangements.

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Section: Resultssupporting

confidence: 91%

“…Chromatin is highly dynamic, and chromatin motions may influence most if not all genome functions including transcription, replication, and repair ( 1 – 5 ). Although the motions of individual chromatin loci are largely stochastic, these motions are primarily driven by adenosine triphosphate–dependent processes, not by heat alone ( 6 – 8 ).…”

mentioning

confidence: 99%

DNA damage reduces heterogeneity and coherence of chromatin motions

Locatelli

Lawrimore

Lin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…A renewed interest in actively-driven chromatin mobility has arisen through studies of the DNA damage response across multiple model systems (Zimmer and Fabre, 2019). Induction of a DNA double-strand break (DSB) leads to an increase in mobility of not only the broken chromosome region, but, surprisingly, the entire genome (Lawrimore et al, 2020; Miné-Hattab and Rothstein, 2013); this effect has been suggested to promote the homology search phase of DSB repair. While many factors contribute to this response, including nuclear and cytoplasmic cytoskeletal proteins (Caridi et al, 2018; Lawrimore et al, 2020; Lottersberger et al, 2015; Oshidari et al, 2018; Schrank et al, 2018; Swartz et al, 2014; Zhurinsky et al, 2019), of note the INO80 nucleosome remodeler appears to play a central role (Cheblal et al, 2020; Hauer et al, 2017; Neumann et al, 2012; Seeber et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Induction of a DNA double-strand break (DSB) leads to an increase in mobility of not only the broken chromosome region, but, surprisingly, the entire genome (Lawrimore et al, 2020; Miné-Hattab and Rothstein, 2013); this effect has been suggested to promote the homology search phase of DSB repair. While many factors contribute to this response, including nuclear and cytoplasmic cytoskeletal proteins (Caridi et al, 2018; Lawrimore et al, 2020; Lottersberger et al, 2015; Oshidari et al, 2018; Schrank et al, 2018; Swartz et al, 2014; Zhurinsky et al, 2019), of note the INO80 nucleosome remodeler appears to play a central role (Cheblal et al, 2020; Hauer et al, 2017; Neumann et al, 2012; Seeber et al, 2013). Indeed, in budding yeast loss of Arp8 disrupts the observed DSB-dependent boost in chromatin mobility (Cheblal et al, 2020; Hauer et al, 2017; Neumann et al, 2012; Seeber et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Bailey

Surovtsev

Williams

et al. 2020

Preprint

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Chromosome conformation capture techniques (e.g Hi-C) reveal that intermediate-scale chromatin organization is comprised of “topologically associating domains” (TADs) on the tens to thousands of kb scale.1–5 The loop extrusion factor (LEF) model6–10 provides a framework for how TADs arise: cohesin or condensin extrude DNA loops, until they encounter boundary elements. Despite recent in vitro studies demonstrating that cohesin and condensin can drive loop formation on (largely) naked DNA11–13, evidence supporting the LEF model in living cells is lacking. Here, we combine experimental measurements of chromatin dynamics in vivo with simulations to further develop the LEF model. We show that the activity of the INO80 nucleosome remodeler enhances chromatin mobility, while cohesin and condensin restrain chromatin mobility. Motivated by these findings and the observations that cohesin is loaded preferentially at nucleosome-depleted transcriptional start sites14–18 and its efficient translocation requires nucleosome remodeling19–23 we propose a new LEF model in which LEF loading and loop extrusion direction depend on the underlying architecture of transcriptional units. Using solely genome annotation without imposing boundary elements, the model predicts TADs that reproduce experimental Hi-C data, including boundaries that are CTCF-poor. Furthermore, polymer simulations based on the model show that LEF-catalyzed loops reduce chromatin mobility, consistent with our experimental measurements. Overall, this work reveals new tenets for the origins of TADs in eukaryotes, driven by transcription-coupled nucleosome remodeling.

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Special issue: Nuclear architecture and chromatin motions in the DNA damage response

Locatelli

Vidi

2020

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Polymer perspective of genome mobilization

Cited by 5 publications

References 152 publications

DNA damage reduces heterogeneity and coherence of chromatin motions

DNA damage reduces heterogeneity and coherence of chromatin motions

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Special issue: Nuclear architecture and chromatin motions in the DNA damage response

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