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A CRISPR-Cas9 screen identifies essential CTCF anchor sites for the mitogenic function of ER-alpha in breast cancer

Korkmaz, Gozde and Manber, Zohar and Marques Lopes, Rui and Prekovic, Stefan and Schuurman, Karianne and Kim, Yongsoo and Teunissen, Hans and Flach, Koen and de Wit, Elzo and Galli, Giorgio and Zwart, Wilbert and Elkon, Ran and Agami, Reuven (2019) A CRISPR-Cas9 screen identifies essential CTCF anchor sites for the mitogenic function of ER-alpha in breast cancer. Nucleic Acids Research. ISSN 0305-10481362-4962

Abstract

Estrogen receptor α (ERα) is an enhancer activating transcriptional factor, a key driver of breast cancer, and a main target for cancer therapy. ER-mediated gene regulation requires proper chromatin-conformation to stimulate physical linkage between ER-bound enhancers and their target promoters. A major determinant of chromatin structure is CTCF that anchors chromatin domains. However, whether CTCF-binding elements (CBEs) are essential for ER mitogenic activity is unknown. To address this question in a global manner, we implemented a CRISPR-based functional genetic screening approach targeting CBEs located in the vicinity of ERα-bound enhancers. We identified four functional CBEs and demonstrated the role of one in inducing chromatin conformation changes in favor of activation of PREX1, a key ERα target gene in breast cancer. Indeed, high PREX1 expression predicted sensitivity to loss of ER, and good survival to anti-hormonal treatment. Altogether, our data show that CTCF-mediated chromatin structure is required for ER mitogenic function.

Item Type: Article
Date Deposited: 27 Aug 2019 00:45
Last Modified: 27 Aug 2019 00:45
URI: https://oak.novartis.com/id/eprint/37528

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