Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging

Science, Journal Year: 2022, Volume and Issue: 376(6592), P. 496 - 501

Published: April 14, 2022

Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF loop-extruding cohesins, but the live dynamics of loop formation stability remain unknown. Here, we directly visualized chromatin looping at

Language: Английский

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Loop stacking organizes genome folding from TADs to chromosomes

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(9), P. 1377 - 1392.e6

Published: May 1, 2023

Language: Английский

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Mitotic chromosomes are self-entangled and disentangle through a topoisomerase-II-dependent two-stage exit from mitosis

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(8), P. 1422 - 1441.e14

Published: March 22, 2024

The topological state of chromosomes determines their mechanical properties, dynamics, and function. Recent work indicated that interphase are largely free entanglements. Here, we use Hi-C, polymer simulations, multi-contact 3C find that, by contrast, mitotic self-entangled. We explore how a self-entangled is converted into an unentangled during exit. Most entanglements removed anaphase/telophase, with remaining ones early G1, in topoisomerase-II-dependent process. Polymer models suggest two-stage disentanglement pathway: first, decondensation condensin loops produces entropic forces bias topoisomerase II activity toward decatenation. At the second stage, released, formation new prevented lower activity, allowing establishment territorial G1 chromosomes. When not experiments models, normal cannot be acquired.

Language: Английский

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Rules of engagement for condensins and cohesins guide mitotic chromosome formation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 18, 2024

Abstract During mitosis, interphase chromatin is rapidly converted into rod-shaped mitotic chromosomes. Using Hi-C, imaging, proteomics and polymer modeling, we determine how the activity interplay between loop-extruding SMC motors accomplishes this dramatic transition. Our work reveals rules of engagement for complexes that are critical allowing cells to refold We find condensin disassembles loop organization by evicting or displacing extrusive cohesin. In contrast, bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion while separating sisters. Studies chromosomes formed cohesin, II I alone in combination allow us develop new models chromosome conformation. these models, loops consecutive not overlapping, implying condensins do freely pass one another but stall upon encountering each other. The dynamics Hi-C interactions morphology reveal during prophase extruded vivo at ∼1-3 kb/sec as they form a disordered discontinuous helical scaffold within individual chromatids.

Language: Английский

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CTCF–CTCF loops and intra-TAD interactions show differential dependence on cohesin ring integrity

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(10), P. 1516 - 1527

Published: Oct. 1, 2022

Language: Английский

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Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 15, 2023

Abstract The first activation of gene expression during development (zygotic genome activation, ZGA) is accompanied by massive changes in chromosome organization. connection between these two processes remains unknown. Using Hi-C for zebrafish embryos, we found that folding starts establishing “fountains”, novel elements organization, emerging selectively at enhancers upon ZGA. polymer simulations, demonstrate fountains can emerge as sites targeted cohesin loading and require two-sided, yet desynchronized, loop extrusion. Specific loss pioneer transcription factors drive ZGA reveals a causal enhancer activity fountain formation. Finally, show early Medaka Xenopus embryos; moreover, cohesin-dependent pattern on mouse embryonic stem cells. Taken together, are the enhancer-specific organization; they constitute starting points development, likely serving loading.

Language: Английский

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Correlative single molecule lattice light sheet imaging reveals the dynamic relationship between nucleosomes and the local chromatin environment

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 16, 2024

Abstract In the nucleus, biological processes are driven by proteins that diffuse through and bind to a meshwork of nucleic acid polymers. To better understand this interplay, we present an imaging platform simultaneously visualize single protein dynamics together with local chromatin environment in live cells. Together super-resolution imaging, new fluorescent probes, biophysical modeling, demonstrate nucleosomes display differential diffusion packing arrangements as density increases whereas viscoelastic properties accessibility interchromatin space remain constant. Perturbing nuclear functions impacts nucleosome diffusive manner is dependent both on relative location within nucleus. Our results support model wherein transcription locally stabilizes while allowing for free exchange proteins. Additionally, they reveal heterogeneity arises from active passive highlight need account different organizational principles when modeling environments.

Language: Английский

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The chromosome folding problem and how cells solve it

Cell, Journal Year: 2024, Volume and Issue: 187(23), P. 6424 - 6450

Published: Nov. 1, 2024

Every cell must solve the problem of how to fold its genome. We describe folded state chromosomes is result combined activity multiple conserved mechanisms. Homotypic affinity-driven interactions lead spatial partitioning active and inactive loci. Molecular motors through loop extrusion. Topological features such as supercoiling entanglements contribute chromosome folding dynamics, tethering loci sub-nuclear structures adds additional constraints. Dramatically diverse conformations observed throughout cycle across tree life can be explained differential regulation implementation these basic propose that first functions are mediate genome replication, compaction, segregation mechanisms have subsequently been co-opted for other roles, including long-range gene regulation, in different conditions, types, species.

Language: Английский

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Bridging spatial and temporal scales of developmental gene regulation

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 92, P. 102328 - 102328

Published: March 12, 2025

The development of multicellular organisms relies on the precise coordination molecular events across multiple spatial and temporal scales. Understanding how information flows from interactions to cellular processes tissue organization during is crucial for explaining remarkable reproducibility complex organisms. This review explores chromatin-encoded transduced localized transcriptional global gene expression patterns, highlighting challenge bridging these We discuss recent experimental findings theoretical frameworks, emphasizing polymer physics as a tool describing relationship between chromatin structure dynamics By integrating perspectives, we aim clarify regulation coordinated levels biological suggest strategies future approaches.

Language: Английский

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Activity-driven chromatin organization during interphase: Compaction, segregation, and entanglement suppression

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(21)

Published: May 16, 2024

In mammalian cells, the cohesin protein complex is believed to translocate along chromatin during interphase form dynamic loops through a process called active loop extrusion. Chromosome conformation capture and imaging experiments have suggested that adopts compact structure with limited interpenetration between chromosomes chromosomal sections. We developed theory demonstrating extrusion causes apparent fractal dimension of cross-over two four at contour lengths on order 30 kilo-base pairs. The anomalously high D = 4 due inability extruded fully relax Compaction longer length scales extends within topologically associated domains (TADs), facilitating gene regulation by distal elements. Extrusion-induced compaction segregates TADs such overlaps are reduced less than 35% increases entanglement strand up factor 50 several Mega-base Furthermore, couples motion conformations formed previously extruding cohesins mean square displacement loci lag times ( Δ t ) tens minutes be proportional 1 / 3 . validate our results hybrid molecular dynamics—Monte Carlo simulations show consistent experimental data. This work provides theoretical basis for organization chromatin, explaining physical reason TAD segregation suppression entanglements which contribute efficient regulation.

Language: Английский

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