ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL

Wutz, Gordana; Ladurner, René; Hilaire, Brian Glenn St; Stocsits, Roman R.; Nagasaka, Kota; Pignard, Benoit; Sanborn, Adrian L.; Tang, Wen; Várnai, Csilla; Ivanov, Miroslav P; Schoenfelder, Stefan; Lelij, Petra van der; Huang, Xingfan; Dürnberger, Gerhard; Roitinger, Elisabeth; Mechtler, Karl; Davidson, Iain F.; Fraser, Peter; Lieberman-Aiden, Erez; Peters, Jan‐Michael

doi:10.7554/elife.52091

Cited by 141 publications

(125 citation statements)

References 85 publications

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“…In other words, introduction of more STAG1 can allow establishment of new loops within Mbp-sized domains. Yet another hint that chromatin interactions change differentially when STAG1 or STAG2 are depleted was provided by Wutz and coworkers in a very recent publication (Wutz et al 2020). They observed longer chromatin loops after depletion of STAG2 for 48 h, presumably mediated by STAG1.…”

Section: Discussionmentioning

confidence: 94%

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

et al. 2020

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Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A, and RAD21, cohesin in somatic cells contains one of two orthologous STAG subunits, STAG1 or STAG2. How these variable subunits affect the function of the cohesin complex is still unclear. STAG1-and STAG2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either STAG1 or STAG2. Following rapid depletion of either subunit, we perform high-resolution Hi-C, gene expression, and sequential ChIP studies to show that STAG1 and STAG2 do not co-occupy individual binding sites and have distinct ways by which they affect looping and gene expression. These findings are further supported by single-molecule localizations via direct stochastic optical reconstruction microscopy (dSTORM) super-resolution imaging. Since somatic and congenital mutations of the STAG subunits are associated with cancer (STAG2) and intellectual disability syndromes with congenital abnormalities (STAG1 and STAG2), we verified STAG1-/STAG2-dependencies using human neural stem cells, hence highlighting their importance in particular disease contexts.

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Section: Discussionmentioning

confidence: 94%

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

et al. 2020

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“…The STAG subunits of cohesin are also capable of binding RNA in the nucleus ( Pan et al, 2020 ). Cohesin associates with DNA by interaction with loading factors NIPBL and MAU2 ( Wendt, 2017 ), its stability on DNA is regulated by the acetyltransferases ESCO1 ( Wutz et al, 2020 ) and ESCO2 ( van der Lelij et al, 2009 ), and its removal is facilitated by PDS5 and WAPL ( Wutz et al, 2017 ; Shintomi and Hirano, 2009 ). The cohesin ring itself acts as a molecular motor to extrude DNA loops, and this activity is thought to underlie its ability to organize the genome ( Vian et al, 2018 ; Mayerova et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Chin

Antony

Ketharnathan

et al. 2020

eLife

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Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21, and STAG2 and screened for synthetic lethality with 3009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin-mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunits stag2b and rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin-mutant cancers.

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“…Similar V H utilization and, separately, RC interaction patterns across the V H locus of IAA-treated CTCF-degron lines and primary pro-B cells suggests related mechanisms. While CTCF depletion provides proof-of-principle that RAG scanning can access distal V H s, physiological modulation of such scanning activity in BM pro-B cells might involve mechanisms that modulate CTCF/CBE impediments 30 – 34 and/or circumvent impediments by modulating cohesin activity 12 , 16 , 35 – 37 . Our findings are consistent with Igh locus contraction in normal pro-B cells and long-range RAG scanning in CTCF-depleted v-Abl cells being inter-related processes.…”

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confidence: 99%

CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning

Lou

et al. 2020

Nature

103

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RAG endonuclease initiates V(D)J recombination in progenitor (pro)-B cells 1 . Upon binding a recombination center (RC)-based J H , RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin, to locate Ds and assemble a DJ H -based RC 2 . CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG-scanning 3 – 5 ; but their inactivation allows scanning to proximal V H s where additional CBEs activate rearrangement and impede scanning any further upstream 5 . Distal V H utilization is thought to involve diffusional RC access following large-scale Igh locus contraction 6 – 8 . Here, we test the potential of linear RAG-scanning to mediate distal V H usage in G1-arrested v-Abl- pro-B cell lines 9 , which undergo robust D-to-J H but little V H -to-DJ H rearrangements, presumably due to lack of locus contraction 2 , 5 . Through an auxin-inducible approach 10 , we degrade the cohesin-component Rad21 10 – 12 or CTCF 12 , 13 in these G1-arrested lines. Rad21 degradation eliminated all V(D)J recombination and RAG-scanning-associated interactions, except RC-located DQ52-to-J H joining in which synapsis occurs by diffusion 2 . Remarkably, while CTCF degradation suppressed most CBE-based chromatin interactions, it promoted robust RC interactions with, and robust V H -to-DJ H joining of, distal V H s, with patterns similar to those of “locus-contracted” primary pro-B cells. Thus, down-modulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG-scanning across the 2.7Mb Igh locus.

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ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL

Cited by 141 publications

References 85 publications

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning

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