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Updated: Oct 30, 2025
Pooled CRISPR-Based Genetic Screens in Mammalian Cells
Published on: September 4, 2019
Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens
Rui Lopes1, Kathleen Sprouffske2, Caibin Sheng2
1Disease area Oncology, Novartis Institute for Biomedical Research, CH-4002 Basel, Switzerland. rui.lopes@novartis.com giorgio.galli@novartis.com.
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.
Insights
Researchers identified key transcriptional regulatory elements (TREs) that estrogen receptor (ER) uses to drive breast cancer progression. These findings illuminate oncogenic transcription factor networks and the noncoding genome in cancer.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Millions of transcriptional regulatory elements (TREs) exist in the human genome, but their specific roles in diseases like cancer are largely unknown.
- Understanding how oncogenic transcription factors (TFs) interact with TREs is crucial for deciphering malignant transcriptional programs.
Purpose of the Study:
- To functionally survey estrogen receptor (ER)-engaged TREs in breast cancer.
- To identify specific TREs and TFs involved in ER-driven oncogenesis.
Main Methods:
- Utilized CRISPR screens and epigenomic profiling to analyze approximately 15,000 TREs bound by ER.
- Integrated genomic and epigenomic data to identify functional regulatory elements.
Main Results:
- Identified ER-controlled TREs enriched with GATA3, TFAP2C, and H3K27Ac signals.
- Demonstrated that TFAP2C is essential for ER-mediated cell proliferation in breast cancer.
Conclusions:
- Revealed a critical oncogenic transcription program driven by ER in breast cancer.
- Provided a framework for mapping regulatory networks and dissecting the function of the noncoding genome in cancer cells.
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