A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation

Gozde Korkmaz, Zohar Manber, Rui Lopes, Stefan Prekovic, Karianne Schuurman, Yongsoo Kim, Hans Teunissen, Koen Flach, Elzo de Wit, Giorgio G. Galli, Wilbert Zwart, Ran Elkon, Reuven Agami

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)9557-9572
Number of pages16
JournalNucleic Acids Research
Volume47
Issue number18
DOIs
Publication statusPublished - 10 Oct 2019

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