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

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.

Original languageEnglish
Article numbereabf5733
JournalScience Advances
Volume7
Issue number27
DOIs
Publication statusPublished - Jul 2021

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