Rapid depletion of CTCF and cohesin proteins reveals dynamic features of chromosome architecture

Liu, Ning Qing; Magnitov, Mikhail D.; Schijns, Marijne M.G.A.; Schaik, Tom van; Weide, Robin H. van der; Teunissen, Hans; Steensel, Bas van; Wit, Elzo de

doi:10.1101/2021.08.27.457977

Cited by 24 publications

(28 citation statements)

References 65 publications

(69 reference statements)

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“…3A and (20, 74)) or between sites of convergent transcription in both yeast (32, 75) and mammalian cells ( Fig. 1A and (37, 38)). Furthermore, in mammalian cells, TSSs and 3’ ends of active genes insulate genomic contacts (20, 29, 74, 76–79) by acting as extrusion boundaries ( Figs.…”

Section: Discussionmentioning

confidence: 96%

“…g ., TSSs, centromeres) (6, 25–28). The emergence of these intergenic “cohesin islands” is particularly prominent in cells in which the cohesin regulators CTCF and Wapl have been depleted (6, 37), but similar accumulation can also occur under physiological conditions, such as senescence (38). In addition, transcription can interfere with cohesin by disrupting its localization at CTCF sites (31), obstructing the growth of cohesin-mediated loops (30, 32), and altering cohesin clustering in 3D (39, 40).…”

Section: Introductionmentioning

confidence: 99%

“…Induction of genes redistributes cohesin downstream (i.e., in the direction of transcription) (25,28,36), and cohesin has been observed to accumulate between active convergently transcribed genes, away from putative cohesin loading sites (e.g., TSSs, centromeres) (6,(25)(26)(27)(28). The emergence of these intergenic "cohesin islands" is particularly prominent in cells in which the cohesin regulators CTCF and Wapl have been depleted (6,37), but similar accumulation can also occur under physiological conditions, such as senescence (38). In addition, transcription can interfere with cohesin by disrupting its localization at CTCF sites (31), obstructing the growth of cohesin-mediated loops (30,32), and altering cohesin clustering in 3D (39,40).…”

Section: Introductionmentioning

confidence: 99%

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Transcription shapes 3D chromatin organization by interacting with loop extrusion

Banigan

Tang

Berg

et al. 2022

Preprint

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Cohesin organizes mammalian interphase chromosomes by reeling chromatin fibers into dynamic loops (Banigan and Mirny, 2020; Davidson et al., 2019; Kim et al., 2019; Yatskevich et al., 2019). "Loop extrusion" is obstructed when cohesin encounters a properly oriented CTCF protein (Busslinger et al., 2017; de Wit et al., 2015; Fudenberg et al., 2016; Nora et al., 2017; Sanborn et al., 2015; Wutz et al., 2017), and recent work indicates that other factors, such as the replicative helicase MCM (Dequeker et al., 2020), can also act as barriers to loop extrusion. It has been proposed that transcription relocalizes (Busslinger et al., 2017; Glynn et al., 2004; Lengronne et al., 2004) or interferes with cohesin (Heinz et al., 2018; Jeppsson et al., 2020; Valton et al., 2021; S. Zhang et al., 2021), and that active transcription start sites function as cohesin loading sites (Busslinger et al., 2017; Kagey et al., 2010; Zhu et al., 2021; Zuin et al., 2014), but how these effects, and transcription in general, shape chromatin is unknown. To determine whether transcription can modulate loop extrusion, we studied cells in which the primary extrusion barriers could be removed by CTCF depletion and cohesin's residence time and abundance on chromatin could be increased by Wapl knockout. We found evidence that transcription directly interacts with loop extrusion through a novel "moving barrier" mechanism, but not by loading cohesin at active promoters. Hi-C experiments showed intricate, cohesin-dependent genomic contact patterns near actively transcribed genes, and in CTCF-Wapl double knockout (DKO) cells (Busslinger et al., 2017), genomic contacts were enriched between sites of transcription-driven cohesin localization ("cohesin islands"). Similar patterns also emerged in polymer simulations in which transcribing RNA polymerases (RNAPs) acted as "moving barriers" by impeding, slowing, or pushing loop-extruding cohesins. The model predicts that cohesin does not load preferentially at promoters and instead accumulates at TSSs due to the barrier function of RNAPs. We tested this prediction by new ChIP-seq experiments, which revealed that the "cohesin loader" Nipbl (Ciosk et al., 2000) co-localizes with cohesin, but, unlike in previous reports (Busslinger et al., 2017; Kagey et al., 2010; Zhu et al., 2021; Zuin et al., 2014), Nipbl did not accumulate at active promoters. We propose that RNAP acts as a new type of barrier to loop extrusion that, unlike CTCF, is not stationary in its precise genomic position, but is itself dynamically translocating and relocalizes cohesin along DNA. In this way, loop extrusion could enable translocating RNAPs to maintain contacts with distal regulatory elements, allowing transcriptional activity to shape genomic functional organization.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcription shapes 3D chromatin organization by interacting with loop extrusion

Banigan

Tang

Berg

et al. 2022

Preprint

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“…All cell lines are based on E14 mouse embryonic stem cells (mESCs). WAPL-AID-eGFP mESCs 38 were kindly provided by Elzo de Wit (Netherlands Cancer Institute). All cell lines for the dual array imaging approach are based on the double-CTCF knockout cell line described in Zuin et al 3 .…”

Section: Methodsmentioning

confidence: 99%

Live-cell imaging and physical modeling reveal control of chromosome folding dynamics by cohesin and CTCF

Mach

Kos

Zhan

et al. 2022

Preprint

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Physical proximity between genomic sequences in mammalian chromosomes controls key biological processes such as transcriptional regulation and DNA repair. Yet it is currently unknown if chromosomal contacts are rare and stable or instead frequent and dynamic, and how they depend on the loop extrusion activity of cohesin or barriers such as CTCF. By imaging chromosomal locations at high spatial and temporal resolution over several hours in living cells, we show that sequences within topological associating domains (TADs) frequently come into physical proximity during the course of a cell cycle and remain close to each other only for a few minutes. Such contacts become nonetheless substantially longer and more frequent in the presence of convergent CTCF sites, resulting in a suppression of variability in chromosome folding in single cells across time. Supported by physical models of chromosome dynamics, our data additionally suggests that individual CTCF-anchored loops last around 10 minutes. The estimates of chromosomal contact dynamics in our study provide a novel quantitative framework to link chromosome structure to function and show that cohesin and CTCF stabilize otherwise highly dynamic chromosome structures to facilitate selected subsets of chromosomal interactions.

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“…WAPL depletion causes an increase in loop stability, with an accumulation of axial elements and weakening of compartments [21,24]. Depletion of Cohesin causes a large fraction of TADs and loops to disappear [24][25][26]. Similarly, depletion of CTCF induces loss of loops and TADs [24,27].…”

Section: Introductionmentioning

confidence: 99%

MoDLE: High-performance stochastic modeling of DNA loop extrusion interactions

Rossini

Kumar

Mathelier

et al. 2022

Preprint

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DNA loop extrusion emerges as a key process establishing genome structure and function. We introduce MoDLE, a computational tool for fast, stochastic modeling of molecular contacts from DNA loop extrusion capable of simulating realistic contact patterns genome wide in a few minutes. MoDLE accurately simulates contact maps in concordance with existing molecular dynamics approaches and with Micro-C data, and does so orders of magnitude faster than existing approaches. MoDLE runs efficiently on machines ranging from laptops to high performance computing clusters, and opens up for exploratory and predictive modeling of 3D genome structure in a wide range of settings.

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Rapid depletion of CTCF and cohesin proteins reveals dynamic features of chromosome architecture

Cited by 24 publications

References 65 publications

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Live-cell imaging and physical modeling reveal control of chromosome folding dynamics by cohesin and CTCF

MoDLE: High-performance stochastic modeling of DNA loop extrusion interactions

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