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 (Corresponding author)

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Uittreksel

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.

Originele taal-2Engels
Pagina's (van-tot)9557-9572
Aantal pagina's16
TijdschriftNucleic Acids Research
Volume47
Nummer van het tijdschrift18
DOI's
StatusGepubliceerd - 10 okt 2019

Vingerafdruk

Clustered Regularly Interspaced Short Palindromic Repeats
Estrogen Receptors
Cell Proliferation
Breast Neoplasms
Chromatin
Activating Transcription Factors
Genes
Cell Line

Citeer dit

Korkmaz, G., Manber, Z., Lopes, R., Prekovic, S., Schuurman, K., Kim, Y., ... Agami, R. (2019). A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation. Nucleic Acids Research, 47(18), 9557-9572. https://doi.org/10.1093/nar/gkz675
Korkmaz, Gozde ; Manber, Zohar ; Lopes, Rui ; Prekovic, Stefan ; Schuurman, Karianne ; Kim, Yongsoo ; Teunissen, Hans ; Flach, Koen ; Wit, Elzo de ; Galli, Giorgio G. ; Zwart, Wilbert ; Elkon, Ran ; Agami, Reuven. / A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation. In: Nucleic Acids Research. 2019 ; Vol. 47, Nr. 18. blz. 9557-9572.
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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.",
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Korkmaz, G, Manber, Z, Lopes, R, Prekovic, S, Schuurman, K, Kim, Y, Teunissen, H, Flach, K, Wit, ED, Galli, GG, Zwart, W, Elkon, R & Agami, R 2019, 'A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation', Nucleic Acids Research, vol. 47, nr. 18, blz. 9557-9572. https://doi.org/10.1093/nar/gkz675

A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation. / Korkmaz, Gozde; Manber, Zohar; Lopes, Rui; Prekovic, Stefan; Schuurman, Karianne; Kim, Yongsoo; Teunissen, Hans; Flach, Koen; Wit, Elzo de; Galli, Giorgio G.; Zwart, Wilbert; Elkon, Ran; Agami, Reuven (Corresponding author).

In: Nucleic Acids Research, Vol. 47, Nr. 18, 10.10.2019, blz. 9557-9572.

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

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T1 - A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation

AU - Korkmaz, Gozde

AU - Manber, Zohar

AU - Lopes, Rui

AU - Prekovic, Stefan

AU - Schuurman, Karianne

AU - Kim, Yongsoo

AU - Teunissen, Hans

AU - Flach, Koen

AU - Wit, Elzo de

AU - Galli, Giorgio G.

AU - Zwart, Wilbert

AU - Elkon, Ran

AU - Agami, Reuven

PY - 2019/10/10

Y1 - 2019/10/10

N2 - 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.

AB - 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.

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JO - Nucleic Acids Research

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