Korkmaz, Gozde, Manber, Zohar, Marques Lopes, Rui, Prekovic, Stefan, Schuurman, Karianne, Kim, Yongsoo, Teunissen, Hans, Flach, Koen, de Wit, Elzo, Galli, Giorgio, Zwart, Wilbert, 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