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

Gabriele, Michele; Brandão, Hugo B.; Grosse‐Holz, Simon; Jha, Asmita; Dailey, Gina M; Cattoglio, Claudia; Ts, Hsieh; Mirny, Leonid A.; Zechner, Christoph; Hansen, Anders S.

doi:10.1126/science.abn6583

Cited by 230 publications

(261 citation statements)

References 83 publications

(43 reference statements)

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“…Thus, loop formation requires efficient cohesin loading onto chromatin, while its processivity is restricted by regulated "load-unload" cycles. However, recent live-cell imaging of the mouse Fbn2 locus showed that full looping is rarely achieved and that, most of the time, cohesin-extruded loops within an active domain form without bringing both CTCF boundaries together (Gabriele et al, 2022). This can be explained by the notion that 3D genome architecture results from the antagonistic interplay between loop extrusion and compartmentalization of homotypic (i.e., active-to-active or inactive-to-inactive) chromatin domains (Nuebler et al, 2018;Rada-Iglesias et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Zhang

Uebelmesser

Barbieri

et al. 2022

Preprint

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Mammalian chromosomes are folded by converging and opposing forces. Here, we tested the role of RNAPII across different scales of interphase chromatin folding in a cellular system allowing for its auxin-mediated degradation. We used Micro-C and computational modeling to characterize subsets of loops differentially gained or lost upon RNAPII depletion. Gained loops, extrusion of which was antagonized by RNAPII, almost invariably formed by engaging new or rewired CTCF anchors. Lost loops selectively concerned contacts between enhancers and promoters anchored by RNAPII. Surprisingly, promoter-promoter contacts were almost insensitive to polymerase depletion and sustained cohesin occupancy in its absence. Selective loss of enhancer-promoter contacts explains the repression of most genes. Together, our findings reconcile the role of RNAPII in transcription with that in setting-up regulatory 3D chromatin architectures genome-wide, while also revealing a direct impact on cohesin loop extrusion.

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Section: Introductionmentioning

confidence: 99%

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Zhang

Uebelmesser

Barbieri

et al. 2022

Preprint

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“…Furthermore, single-molecule experiments demonstrated that RNA polymerase (RNAP) can push a passively diffusing cohesin complex along DNA in vitro (41). However, it is not known how transcription-driven cohesin relocalization can be reconciled with now well established observations of active loop extrusion by cohesin (3)(4)(5)42), and what patterns of chromatin organization can emerge from transcription-extrusion interactions.…”

Section: Introductionmentioning

confidence: 99%

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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“…Interestingly, it is in a “partially extruded” state for ∼92% of the time. In such a state, ∼57–61% of the chromatin exists in ∼1–3 cohesin loops while the rest remain un-extruded [21] .…”

Section: Chromatin Hubs: the Biological Sidementioning

confidence: 99%

Chromatin Hubs: A biological and computational outlook

Mora

Huang²,

Jauhari³

et al. 2022

Computational and Structural Biotechnology Journal

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

Cited by 230 publications

References 83 publications

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Chromatin Hubs: A biological and computational outlook

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