The Self-Organizing Genome: Principles of Genome Architecture and Function

Cell, Journal Year: 2020, Volume and Issue: 183(1), P. 28 - 45

Published: Sept. 24, 2020

Language: Английский

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MCM complexes are barriers that restrict cohesin-mediated loop extrusion

Nature, Journal Year: 2022, Volume and Issue: 606(7912), P. 197 - 203

Published: May 18, 2022

Abstract Eukaryotic genomes are compacted into loops and topologically associating domains (TADs) 1–3 , which contribute to transcription, recombination genomic stability 4,5 . Cohesin extrudes DNA that thought lengthen until CTCF boundaries encountered 6–12 Little is known about whether loop extrusion impeded by DNA-bound machines. Here we show the minichromosome maintenance (MCM) complex a barrier restricts in G1 phase. Single-nucleus Hi-C (high-resolution chromosome conformation capture) of mouse zygotes reveals MCM loading reduces CTCF-anchored decreases TAD boundary insulation, suggests before reaching CTCF. This effect extends HCT116 cells, MCMs affect number gene expression. Simulations suggest abundant, randomly positioned partially permeable barriers. Single-molecule imaging shows physical barriers frequently constrain cohesin translocation vitro. Notably, chimeric yeast contain cohesin-interaction motif from human MCM3 induce pausing, indicating ‘active’ with binding sites. These findings raise possibility can arrive at MCMs, determine sites sister chromatid cohesion established. On basis vivo, silico vitro data, conclude distinct shape three-dimensional genome.

Language: Английский

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CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion

Nature, Journal Year: 2023, Volume and Issue: 616(7958), P. 822 - 827

Published: April 19, 2023

Abstract In eukaryotes, genomic DNA is extruded into loops by cohesin 1 . By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs) 2,3 that have important roles in gene regulation and recombination during development disease 1,4–7 How CTCF establishes TAD boundaries to what extent these are permeable unclear 8 Here, address questions, we visualize interactions of single molecules on vitro. We show sufficient block diffusing cohesin, possibly reflecting how cohesive accumulates at boundaries, also loop-extruding boundaries. functions asymmetrically, as predicted; however, dependent tension. Moreover, regulates cohesin’s loop-extrusion activity changing its direction inducing loop shrinkage. Our data indicate not, previously assumed, simply a barrier cohesin-mediated extrusion but an active regulator whereby permeability can be modulated These results reveal mechanistic principles controls genome architecture.

Language: Английский

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The sirtuin-associated human senescence program converges on the activation of placenta-specific gene PAPPA

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(8), P. 991 - 1009.e12

Published: March 13, 2024

Language: Английский

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Intertwining roles of R-loops and G-quadruplexes in DNA repair, transcription and genome organization

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(7), P. 1025 - 1036

Published: June 24, 2024

Language: Английский

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CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 12, 2021

Abstract Vertebrate genomes are partitioned into contact domains defined by enhanced internal frequency and formed two principal mechanisms: compartmentalization of transcriptionally active inactive domains, stalling chromosomal loop-extruding cohesin CTCF bound at domain boundaries. While Drosophila has widespread CTCF, it is currently unclear whether CTCF-dependent exist in flies. We genetically ablate examine impacts on genome folding transcriptional regulation the central nervous system. find that required to form a small fraction all boundaries, while critically controlling expression patterns certain genes supporting system function. also recruits pervasive boundary-associated factor Cp190 CTCF-occupied boundaries co-regulates subset near together with Cp190. These results highlight profound difference CTCF-requirement for flies vertebrates, which large suggest played mutable roles architecture direct gene control during metazoan evolution.

Language: Английский

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TCF-1 promotes chromatin interactions across topologically associating domains in T cell progenitors

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(7), P. 1052 - 1062

Published: June 20, 2022

Language: Английский

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Active enhancers strengthen insulation by RNA-mediated CTCF binding at chromatin domain boundaries

Genome Research, Journal Year: 2023, Volume and Issue: 33(1), P. 1 - 17

Published: Jan. 1, 2023

Vertebrate genomes are partitioned into chromatin domains or topologically associating (TADs), which typically bound by head-to-head pairs of CTCF binding sites. Transcription at domain boundaries correlates with better insulation; however, it is not known whether the boundary transcripts themselves contribute to function. Here we characterize boundary-associated RNAs genome-wide, focusing on disease-relevant INK4a/ARF and MYC TAD. Using site deletions RNA knockdowns, observe that facilitate recruitment clustering TAD borders. The resulting enrichment enhances insulation, enhancer–promoter interactions, gene expression. Importantly, knockdown results in loss insulation enhancer CRISPRi promoters, show active enhancers, but induce transcription, thus defining a novel class regulatory RNAs.

Language: Английский

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Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 12, 2023

Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites the CTCF insulator protein. Here we determine how this clustering contributes to blocking extrusion and insulation between TADs. We identify enrichment three features at strong boundaries, strongly bound closely spaced peaks, a further DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells normal perturbed binding, establish individual contribute but an incomplete manner. When clustered, thus create stepwise neighboring Based on results, propose model whereby multiple instances temporal

Language: Английский

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Cis-regulatory chromatin contacts form de novo in the absence of loop extrusion

Published: Jan. 13, 2025

SUMMARY NIPBL promotes chromatin loop extrusion by the cohesin complex until it stalls at convergently oriented CTCF sites, leading to formation of structural loops. However, what extent contributes establishment vs maintenance cis -regulatory element (CRE) connectivity is poorly understood. Here, we explored de novo folding patterns mitosis-to-G1-phase transition upon acute loss. depletion primarily impaired cohesin-mediated loops with dependence being proportional length. In contrast, majority CRE were established independently regardless slowed re-formation weak enhancers. Transcription genes NIPBL-independent anchors was activated normally in absence NIPBL. sum, most regulatory contacts and gene transcription following mitotic exit independent extrusion.

Language: Английский

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