Chromatin Extrusion Explains Key Features of Loop and Domain Formation in Wild‐type and Engineered Genomes

Sanborn, Adrian L.; Rao, Suhas S.P.; Huang, Shaoming; Durand, Neva C.; Huntley, Miriam; Jewett, Andrew I.; Bochkov, Ivan D.; Chinnappan, Dharmaraj; Cutkosky, Ashok; Li, Jian; Geeting, Kristopher; Gnirke, Andreas; Melnikov, Alexandre; McKenna, Douglas; Stamenova, Elena K.; Lander, Eric S.; Aiden, E

doi:10.1096/fasebj.30.1_supplement.588.1

Cited by 121 publications

(199 citation statements)

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“…The interactions between the many transcription factors and co-factors which might form the bridging complexes involved in cis-regulatory binding are not well characterized, and the DHS approximation avoids the need to make any assumptions. One factor that most certainly has a chromatin architectural role is the CCCTC-binding factor (CTCF) [4,35,40,[42][43][44]. This protein is thought to form dimers which drive looping between some of its specific binding sites scattered along the chromosomes of eukaryotic organisms.…”

Section: Introductionmentioning

confidence: 99%

“…This protein is thought to form dimers which drive looping between some of its specific binding sites scattered along the chromosomes of eukaryotic organisms. In particular, convergent CTCF binding sites have been proposed to delimit the extent of chromatin domains, which might be extruded through a looping complex, possibly comprising cohesin [40,44,45]. CTCF is therefore a bridge with an architectural role, and has indeed been dubbed a "global genome organizer" [4,35,42].…”

Section: Introductionmentioning

confidence: 99%

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Predicting the three-dimensional folding of cis-regulatory regions in mammalian genomes using bioinformatic data and polymer models

et al. 2016

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The three-dimensional (3D) organization of chromosomes can be probed using methods like Capture-C. However, it is unclear how such population-level data relate to the organization within a single cell, and the mechanisms leading to the observed interactions are still largely obscure. We present a polymer modeling scheme based on the assumption that chromosome architecture is maintained by protein bridges, which form chromatin loops. To test the model, we perform FISH experiments and compare with Capture-C data. Starting merely from the locations of protein binding sites, our model accurately predicts the experimentally observed chromatin interactions, revealing a population of 3D conformations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0909-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predicting the three-dimensional folding of cis-regulatory regions in mammalian genomes using bioinformatic data and polymer models

et al. 2016

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“…Enhancer/promoter interactions mediated by CTCF and cohesin have been proposed to result from actively extruding cohesin molecules on DNA which are preferentially stalled by CTCF at convergently oriented CBSs [23][24][25] . In the context of the Pcdha gene cluster, Pcdha 1-12 promoters/exons bear two CBSs (pCBS and eCBS, respectively), while Pcdhac1 solely has a pCBS (Fig.…”

Section: Cohesin Extrusion In the Pcdha Gene Cluster Randomizes Promo...mentioning

confidence: 99%

Cohesin erases genomic-proximity biases to drive stochastic Protocadherin expression for proper neural wiring

Canzio

Kiefer

Servito

et al. 2022

Preprint

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Clustered Protocadherin (Pcdh) proteins act as cell-surface recognition barcodes for neural circuit formation. Neurites expressing the same barcode repel each other, but this mechanism is deployed in two different ways. For instance, convergence of olfactory sensory neuron (OSN) projections requires stochastic expression of distinct Pcdh isoforms in individual cells, while tiling of neural arbors of serotonergic neurons (5-HTs) requires expression of the same isoform, Pcdhαc2. Despite their essential role, however, the molecular mechanisms of cell-type specific Pcdh barcoding remain a mystery. Here, we uncover a new role of cohesin: that of regulating distance-independent enhancer-promoter interactions to enable random Pcdh isoform choice via DNA loop extrusion in OSNs. Remarkably, this step mediates DNA demethylation of Pcdh promoters and their CTCF binding sites, thus directing CTCF to the chosen promoter. In contrast, the uniform pattern of Pcdh expression in 5-HTs is achieved through conventional cohesin-independent, distance-dependent enhancer/promoter interactions, that favor choice of the nearest isoform. Thus, cell-type specific cohesin deployment converts a distance-dependent and deterministic regulatory logic into a distance-independent and stochastic one. We propose that this mechanism provides an elegant strategy to achieve distinct patterns of Pcdh expression that generate wiring instructions to meet the connectivity requirements of different neural classes.

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“…According to the loop extrusion model, the nanometersize molecular machines organize chromosomes in nucleus of living cells by producing dynamically expanding chromatin loops [1,2]. The molecular dynamics simulations of chromatin fiber subject to loop extrusion allow to reproduce the in vivo 3D chromosome structures and explain the origin of interphase domains observed in experimental Hi-C data [3][4][5][6]. Importantly, being originally proposed as a hypothetical molecular mechanism, the loop extrusion process has been observed in the recent single-molecule experiments in vitro [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Conformational statistics of non-equilibrium polymer loops in Rouse model with active loop extrusion

Starkov,

Parfenyev,

Belan

2021

Preprint

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Motivated by the recent experimental observations of the DNA loop extrusion by protein motors, in this paper we investigate the statistical properties of the growing polymer loops within the ideal chain model. The loop conformation is characterised statistically by the mean gyration radius and the pairwise contact probabilities. It turns out that a single dimensionless parameter, which is given by the ratio of the loop relaxation time over the time elapsed since the start of extrusion, controls the crossover between near-equilibrium and highly non-equilibrium asymptotics in statistics of the extruded loop. Besides, we show that two-sided and one-sided loop extruding motors produce the loops with almost identical properties. Our predictions are based on two rigorous semi-analytical methods accompanied by asymptotic analysis of slow and fast extrusion limits.

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Chromatin Extrusion Explains Key Features of Loop and Domain Formation in Wild‐type and Engineered Genomes

Cited by 121 publications

References 19 publications

Predicting the three-dimensional folding of cis-regulatory regions in mammalian genomes using bioinformatic data and polymer models

Predicting the three-dimensional folding of cis-regulatory regions in mammalian genomes using bioinformatic data and polymer models

Cohesin erases genomic-proximity biases to drive stochastic Protocadherin expression for proper neural wiring

Conformational statistics of non-equilibrium polymer loops in Rouse model with active loop extrusion

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