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

ABSTRACT: Estrogen receptor ? (ER?) is an enhancer activating transcription factor, a key driver of breast cancer and a main target for cancer therapy. ER?-mediated gene regulation requires proper chromatin-conformation to facilitate interactions between ER?-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 ER?-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 ER?-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 ER? target gene in breast cancer. Indeed, high PREX1 expression is a bona-fide marker of ER?-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 ER?- driven breast cancer cell proliferation.

SUBMITTER: Korkmaz G 

PROVIDER: S-EPMC6765117 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature