Mediator recruits the cohesin loader Scc2 to RNA Pol II-transcribed genes and promotes sister chromatid cohesion

Mattingly, Mark; Seidel, Chris; Muñoz, Sofía; Hao, Yan; Zhang, Ying; Wen, Zhihui; Florens, Laurence; Uhlmann, Frank; Gerton, Jennifer L.

doi:10.1016/j.cub.2022.05.019

Cited by 13 publications

(7 citation statements)

References 79 publications

(143 reference statements)

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“…Hi-C studies that followed this early work found Mediator and RNAPII to be dispensable for 3D chromatin folding (Jiang et al, 2020;El Khattabi et al, 2019). This is now challenged by MCC data showing loss of enhancer-promoter contacts following acute depletion of Mediator (Preprint: Ramasamy et al, 2022) and by decreased cohesin binding to RNAPII-transcribed genes following depletion of the yeast Med14 subunit (Mattingly et al, 2022). These new observations, together with the Micro-C analysis we present here, put the still-debated role of RNAPII in 3D chromatin folding in a different light.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Zhang

Uebelmesser

Barbieri

et al. 2022

Preprint

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“…In many organisms, including C. elegans , NIPBL binds to active enhancers (Kranz et al 2013; Busslinger et al 2017; Zhu et al 2021). In yeast, NIPBL interacts with and is recruited by the mediator complex (Mattingly et al 2022). Therefore, it is possible that transcription factors interaction with the mediator recruits NIPBL to load cohesin at active enhancers.…”

Section: Discussionmentioning

confidence: 99%

Cohesin mediated loop extrusion from active enhancers form chromatin jets inC. elegans

Kim,

Wang,

Ercan

2023

Preprint

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In mammals, cohesin and CTCF organize the 3D genome into topologically associated domains (TADs) to regulate communication between cis-regulatory elements. However, many organisms, including S. cerevisiae, C. elegans, and A. thaliana lack CTCF. Here, we use C. elegans as a model to investigate the function of cohesin in 3D genome organization in an animal without CTCF. We use auxin-inducible degradation to acutely deplete SMC-3 or its negative regulator WAPL-1 from somatic cells. Using Hi-C data, we identify a cohesin-dependent 3D genome feature termed chromatin jets (aka fountains), also observed in zebrafish and mammalian genomes. The jets emerge from NIPBL occupied segments, and the trajectory of the jets coincides with cohesin binding. The spreading of cohesin from jet origins depends on a fully intact cohesin complex and is extended upon WAPL-1 depletion. These results support the idea that cohesin is preferentially loaded at NIPBL occupied sites, from which cohesin loop extrudes in an effectively two-sided manner. The location of putative loading sites coincides with active enhancers and the pattern of chromatin jets correlates with transcription. We propose that in the absence of CTCF, preferential loading of cohesin at enhancers is a conserved mechanism of genome organization that regulates the interaction of gene regulatory elements in 3D.

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“…They might also be accessible for second DNA capture by cohesins that were previously topologically loaded close-by, e.g. at nucleosome-free promoter regions 48,[60][61][62] (Fig. 4c).…”

Section: Discussionmentioning

confidence: 99%

Cohesin chromatin loop formation by an extrinsic motor

Guérin,

Barrington,

Pobegalov

et al. 2023

Preprint

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The ring-shaped cohesin complex topologically entraps two DNAs to establish sister chromatid cohesion1–3. Cohesin also shapes the interphase chromatin landscape with wide-ranging implications for gene regulation4–7, which cohesin is thought to achieve by actively extruding DNA loops without topologically entrapping DNA8–11. The ‘loop extrusion’ hypothesis finds motivation fromin vitroobservations12–14– whether this process underliesin vivochromatin loop formation remains untested. Here, using the budding yeastS. cerevisiae, we generate cohesin variants that have lost their ability to extrude DNA loops but retain their ability to topologically entrap DNA. Analysis of these variants suggests thatin vivochromatin loops form independently of loop extrusion. Instead, we find that transcription promotes loop formation, as well as acts as an extrinsic motor that expands these loops and defines their ultimate positions. Our results necessitate a re-evaluation of the loop extrusion model and point to an alternative mechanism for cohesin-dependent chromatin organisation. We propose that cohesin, akin to sister chromatid cohesion establishment at replication forks, forms chromatin loops by DNA-DNA capture at places of transcription, thus unifying cohesin’s two roles in chromosome segregation and interphase genome organisation.

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Mediator recruits the cohesin loader Scc2 to RNA Pol II-transcribed genes and promotes sister chromatid cohesion

Cited by 13 publications

References 79 publications

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Cohesin mediated loop extrusion from active enhancers form chromatin jets inC. elegans

Cohesin chromatin loop formation by an extrinsic motor

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