STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma.

Bone Neoplasms / genetics CCCTC-Binding Factor / chemistry Cell Cycle Proteins / genetics Cell Line, Tumor Cell Movement / genetics Chromatin Immunoprecipitation Chromosomal Proteins, Non-Histone / metabolism Enhancer Elements, Genetic Gene Expression Regulation, Neoplastic Histones / metabolism Humans Loss of Function Mutation Lysine / metabolism Oncogene Proteins, Fusion / genetics Promoter Regions, Genetic Sarcoma, Ewing / genetics Cohesins
CTCF Ewing sarcoma STAG1 STAG2 anchorage chromatin extrusion cohesin enhancer loop migration

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
14 06 2021
Historique:
received: 02 12 2019
revised: 31 08 2020
accepted: 02 04 2021
pubmed: 1 5 2021
medline: 18 12 2021
entrez: 30 4 2021
Statut: ppublish

Résumé

STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, a childhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly alters the anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting the expression of genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulation of cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewing cells previously observed in EWSR1-FLI1

Identifiants

DOI: 10.1016/j.ccell.2021.04.001 PMID: 33930311
pubmed: 33930311
pii: S1535-6108(21)00208-7
doi: 10.1016/j.ccell.2021.04.001
pii:
doi:

Substances chimiques

CCCTC-Binding Factor 0
CTCF protein, human 0
Cell Cycle Proteins 0
Chromosomal Proteins, Non-Histone 0
EWSR1-FLI1 fusion protein, human 0
Histones 0
Oncogene Proteins, Fusion 0
STAG2 protein, human 0
Lysine K3Z4F929H6

Types de publication

Journal Article Research Support, Non-U.S. Gov't Video-Audio Media

Langues

eng

Sous-ensembles de citation

IM

Pagination

810-826.e9

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Didier Surdez (D)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France. Electronic address: didier.surdez@curie.fr.

Sakina Zaidi (S)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France.

Sandrine Grossetête (S)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France.

Karine Laud-Duval (K)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France.

Anna Sole Ferre (AS)

INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer and Université de Paris, Imagine Institute, 75005 Paris, France.

Lieke Mous (L)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France.

Thomas Vourc'h (T)

UMR 168, Biology Inspired Physics at Mesoscales, PSL Research University, Institut Curie Research Centre, 75005 Paris, France.

Franck Tirode (F)

Univ Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Cancer Research Center of Lyon, 69008 Lyon, France.

Gaelle Pierron (G)

Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, 75005 Paris, France.

Virginie Raynal (V)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France; Institut Curie Genomics of Excellence (ICGex) Platform, PSL Université, Institut Curie Research Centre, 75005 Paris, France.

Sylvain Baulande (S)

Institut Curie Genomics of Excellence (ICGex) Platform, PSL Université, Institut Curie Research Centre, 75005 Paris, France.

Erika Brunet (E)

INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer and Université de Paris, Imagine Institute, 75005 Paris, France.

Véronique Hill (V)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France.

Olivier Delattre (O)

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France; Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, 75005 Paris, France. Electronic address: olivier.delattre@curie.fr.

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Classifications MeSH

questionsmedicales.fr › Maladies ostéomusculaires › Maladies osseuses › Tumeurs osseuses › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Facteur de liaison à la séquence CCCTC › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Phénomènes physiologiques › Mouvement cellulaire › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Techniques d'investigation › Techniques immunologiques › Immunoprécipitation › Immunoprécipitation de la chromatine › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation perte de fonction › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés essentiels › Lysine › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines de fusion oncogènes › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › STAG2 mutations alter CTCF-anchored loop...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu conjonctif et des tissus mous › Sarcomes › Ostéosarcome › Sarcome d'Ewing › STAG2 mutations alter CTCF-anchored loop...