Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens

Rui Lopes; Kathleen Sprouffske; Caibin Sheng; Esther C H Uijttewaal; Adriana Emma Wesdorp; Jan Dahinden; Simon Wengert; Juan Diaz-Miyar; Umut Yildiz; Melusine Bleu; Verena Apfel; Fanny Mermet-Meillon; Rok Krese; Mathias Eder; André Vidas Olsen; Philipp Hoppe; Judith Knehr; Walter Carbone; Rachel Cuttat; Annick Waldt; Marc Altorfer; Ulrike Naumann; Joachim Weischenfeldt; Antoine deWeck; Audrey Kauffmann; Guglielmo Roma; Dirk Schübeler; Giorgio G Galli

doi:10.1126/sciadv.abf5733

Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens

Rui Lopes, Kathleen Sprouffske, Caibin Sheng, Esther C H Uijttewaal, Adriana Emma Wesdorp, Jan Dahinden, Simon Wengert, Juan Diaz-Miyar, Umut Yildiz, Melusine Bleu, Verena Apfel, Fanny Mermet-Meillon, Rok Krese, Mathias Eder, André Vidas Olsen, Philipp Hoppe, Judith Knehr, Walter Carbone, Rachel Cuttat, Annick WaldtMarc Altorfer, Ulrike Naumann, Joachim Weischenfeldt, Antoine deWeck, Audrey Kauffmann, Guglielmo Roma, Dirk Schübeler, Giorgio G Galli

Finsenlaboratoriet

20 Citationer (Scopus)

Abstract

Millions of putative transcriptional regulatory elements (TREs) have been cataloged in the human genome, yet their functional relevance in specific pathophysiological settings remains to be determined. This is critical to understand how oncogenic transcription factors (TFs) engage specific TREs to impose transcriptional programs underlying malignant phenotypes. Here, we combine cutting edge CRISPR screens and epigenomic profiling to functionally survey ≈15,000 TREs engaged by estrogen receptor (ER). We show that ER exerts its oncogenic role in breast cancer by engaging TREs enriched in GATA3, TFAP2C, and H3K27Ac signal. These TREs control critical downstream TFs, among which TFAP2C plays an essential role in ER-driven cell proliferation. Together, our work reveals novel insights into a critical oncogenic transcription program and provides a framework to map regulatory networks, enabling to dissect the function of the noncoding genome of cancer cells.

Originalsprog	Engelsk
Artikelnummer	eabf5733
Tidsskrift	Science Advances
Vol/bind	7
Udgave nummer	27
DOI	https://doi.org/10.1126/sciadv.abf5733
Status	Udgivet - jul. 2021

Adgang til dokumentet

10.1126/sciadv.abf5733

Andre filer og links

Link to publication in Scopus

Citationsformater

Lopes, R., Sprouffske, K., Sheng, C., Uijttewaal, E. C. H., Wesdorp, A. E., Dahinden, J., Wengert, S., Diaz-Miyar, J., Yildiz, U., Bleu, M., Apfel, V., Mermet-Meillon, F., Krese, R., Eder, M., Olsen, A. V., Hoppe, P., Knehr, J., Carbone, W., Cuttat, R., ... Galli, G. G. (2021). Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens. Science Advances, 7(27), Artikel eabf5733. https://doi.org/10.1126/sciadv.abf5733

Lopes, R, Sprouffske, K, Sheng, C, Uijttewaal, ECH, Wesdorp, AE, Dahinden, J, Wengert, S, Diaz-Miyar, J, Yildiz, U, Bleu, M, Apfel, V, Mermet-Meillon, F, Krese, R, Eder, M, Olsen, AV, Hoppe, P, Knehr, J, Carbone, W, Cuttat, R, Waldt, A, Altorfer, M, Naumann, U, Weischenfeldt, J, deWeck, A, Kauffmann, A, Roma, G, Schübeler, D & Galli, GG 2021, 'Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens', Science Advances, bind 7, nr. 27, eabf5733. https://doi.org/10.1126/sciadv.abf5733

@article{45e7af9d7f404d7bbb8eb44f2ddac253,

title = "Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens",

abstract = "Millions of putative transcriptional regulatory elements (TREs) have been cataloged in the human genome, yet their functional relevance in specific pathophysiological settings remains to be determined. This is critical to understand how oncogenic transcription factors (TFs) engage specific TREs to impose transcriptional programs underlying malignant phenotypes. Here, we combine cutting edge CRISPR screens and epigenomic profiling to functionally survey ≈15,000 TREs engaged by estrogen receptor (ER). We show that ER exerts its oncogenic role in breast cancer by engaging TREs enriched in GATA3, TFAP2C, and H3K27Ac signal. These TREs control critical downstream TFs, among which TFAP2C plays an essential role in ER-driven cell proliferation. Together, our work reveals novel insights into a critical oncogenic transcription program and provides a framework to map regulatory networks, enabling to dissect the function of the noncoding genome of cancer cells.",

author = "Rui Lopes and Kathleen Sprouffske and Caibin Sheng and Uijttewaal, {Esther C H} and Wesdorp, {Adriana Emma} and Jan Dahinden and Simon Wengert and Juan Diaz-Miyar and Umut Yildiz and Melusine Bleu and Verena Apfel and Fanny Mermet-Meillon and Rok Krese and Mathias Eder and Olsen, {Andr{\'e} Vidas} and Philipp Hoppe and Judith Knehr and Walter Carbone and Rachel Cuttat and Annick Waldt and Marc Altorfer and Ulrike Naumann and Joachim Weischenfeldt and Antoine deWeck and Audrey Kauffmann and Guglielmo Roma and Dirk Sch{\"u}beler and Galli, {Giorgio G}",

note = "Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",

year = "2021",

month = jul,

doi = "10.1126/sciadv.abf5733",

language = "English",

volume = "7",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "27",

}

TY - JOUR

T1 - Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens

AU - Lopes, Rui

AU - Sprouffske, Kathleen

AU - Sheng, Caibin

AU - Uijttewaal, Esther C H

AU - Wesdorp, Adriana Emma

AU - Dahinden, Jan

AU - Wengert, Simon

AU - Diaz-Miyar, Juan

AU - Yildiz, Umut

AU - Bleu, Melusine

AU - Apfel, Verena

AU - Mermet-Meillon, Fanny

AU - Krese, Rok

AU - Eder, Mathias

AU - Olsen, André Vidas

AU - Hoppe, Philipp

AU - Knehr, Judith

AU - Carbone, Walter

AU - Cuttat, Rachel

AU - Waldt, Annick

AU - Altorfer, Marc

AU - Naumann, Ulrike

AU - Weischenfeldt, Joachim

AU - deWeck, Antoine

AU - Kauffmann, Audrey

AU - Roma, Guglielmo

AU - Schübeler, Dirk

AU - Galli, Giorgio G

N1 - Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2021/7

Y1 - 2021/7

N2 - Millions of putative transcriptional regulatory elements (TREs) have been cataloged in the human genome, yet their functional relevance in specific pathophysiological settings remains to be determined. This is critical to understand how oncogenic transcription factors (TFs) engage specific TREs to impose transcriptional programs underlying malignant phenotypes. Here, we combine cutting edge CRISPR screens and epigenomic profiling to functionally survey ≈15,000 TREs engaged by estrogen receptor (ER). We show that ER exerts its oncogenic role in breast cancer by engaging TREs enriched in GATA3, TFAP2C, and H3K27Ac signal. These TREs control critical downstream TFs, among which TFAP2C plays an essential role in ER-driven cell proliferation. Together, our work reveals novel insights into a critical oncogenic transcription program and provides a framework to map regulatory networks, enabling to dissect the function of the noncoding genome of cancer cells.

AB - Millions of putative transcriptional regulatory elements (TREs) have been cataloged in the human genome, yet their functional relevance in specific pathophysiological settings remains to be determined. This is critical to understand how oncogenic transcription factors (TFs) engage specific TREs to impose transcriptional programs underlying malignant phenotypes. Here, we combine cutting edge CRISPR screens and epigenomic profiling to functionally survey ≈15,000 TREs engaged by estrogen receptor (ER). We show that ER exerts its oncogenic role in breast cancer by engaging TREs enriched in GATA3, TFAP2C, and H3K27Ac signal. These TREs control critical downstream TFs, among which TFAP2C plays an essential role in ER-driven cell proliferation. Together, our work reveals novel insights into a critical oncogenic transcription program and provides a framework to map regulatory networks, enabling to dissect the function of the noncoding genome of cancer cells.

UR - http://www.scopus.com/inward/record.url?scp=85109278247&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abf5733

DO - 10.1126/sciadv.abf5733

M3 - Journal article

C2 - 34215580

SN - 2375-2548

VL - 7

JO - Science Advances

JF - Science Advances

IS - 27

M1 - eabf5733

ER -

Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens

Abstract

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater