A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
10 10 2019
10 10 2019
Historique:
accepted:
24
07
2019
revised:
11
07
2019
received:
29
01
2019
pubmed:
3
8
2019
medline:
4
12
2019
entrez:
3
8
2019
Statut:
ppublish
Résumé
Estrogen receptor α (ERα) is an enhancer activating transcription factor, a key driver of breast cancer and a main target for cancer therapy. ERα-mediated gene regulation requires proper chromatin-conformation to facilitate interactions between ERα-bound enhancers and their target promoters. A major determinant of chromatin structure is the CCCTC-binding factor (CTCF), that dimerizes and together with cohesin stabilizes chromatin loops and forms the boundaries of topologically associated domains. However, whether CTCF-binding elements (CBEs) are essential for ERα-driven cell proliferation is unknown. To address this question in a global manner, we implemented a CRISPR-based functional genetic screen targeting CBEs located in the vicinity of ERα-bound enhancers. We identified four functional CBEs and demonstrated the role of one of them in inducing chromatin conformation changes in favor of activation of PREX1, a key ERα target gene in breast cancer. Indeed, high PREX1 expression is a bona-fide marker of ERα-dependency in cell lines, and is associated with good outcome after anti-hormonal treatment. Altogether, our data show that distinct CTCF-mediated chromatin structures are required for ERα- driven breast cancer cell proliferation.
Identifiants
pubmed: 31372638
pii: 5542888
doi: 10.1093/nar/gkz675
pmc: PMC6765117
doi:
Substances chimiques
CCCTC-Binding Factor
0
CTCF protein, human
0
Chromatin
0
ESR1 protein, human
0
Estrogen Receptor alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9557-9572Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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