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Discovery and Functional Characterization of Pro-growth Enhancers in Human Cancer Cells

Poshen B. Chen, Patrick C. Fiaux, Bin Li, Kai Zhang, Naoki Kubo, Shan Jiang, Rong Hu, Sihan Wu, Mengchi Wang, Wei Wang, View ORCID ProfileGraham McVicker, Paul S. Mischel, Bing Ren
doi: https://doi.org/10.1101/2021.02.04.429675
Poshen B. Chen
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
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Patrick C. Fiaux
2Bioinformatics and System Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA
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Bin Li
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
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Kai Zhang
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
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Naoki Kubo
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
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Shan Jiang
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
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Rong Hu
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
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Sihan Wu
4Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
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Mengchi Wang
2Bioinformatics and System Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA
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Wei Wang
2Bioinformatics and System Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA
4Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
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Graham McVicker
3Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
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  • ORCID record for Graham McVicker
Paul S. Mischel
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
4Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
5Department of Pathology, University of California at San Diego, La Jolla, CA, USA
6Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA
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Bing Ren
1Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA
4Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
6Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA
7Institute of Genome Medicine, UCSD school of Medicine, La Jolla, CA, USA
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  • For correspondence: biren@ucsd.edu
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Abstract

Precision medicine depends critically on developing treatment strategies that can selectively target cancer cells with minimal adverse effects. Identifying unique transcriptional regulators of oncogenic signaling, and targeting cancer-cell-specific enhancers that may be active only in specific tumor cell lineages, could provide the necessary high specificity, but a scarcity of functionally validated enhancers in cancer cells presents a significant hurdle to this strategy. We address this limitation by carrying out large-scale functional screens for pro-growth enhancers using highly multiplexed CRISPR-based perturbation and sequencing in multiple cancer cell lines. We used this strategy to identify 488 pro-growth enhancers in a colorectal cancer cell line and 22 functional enhancers for the MYC and MYB key oncogenes in an additional nine cancer cell lines. The majority of pro-growth enhancers are accessible and presumably active only in cancer cells but not in normal tissues, and are enriched for elements associated with poor prognosis in colorectal cancer. We further identify master transcriptional regulators and demonstrate that the cancer pro-growth enhancers are modulated by lineage-specific transcription factors acting downstream of growth signaling pathways. Our results uncover context-specific, potentially actionable pro-growth enhancers from cancer cells, yielding insight into altered oncogenic transcription and revealing potential therapeutic targets for cancer treatment.

Competing Interest Statement

B.R. is a co-founder and consultant for Arima Genomics, Inc., and a co-founder of Epigenome Technologies, Inc.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted February 05, 2021.
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Discovery and Functional Characterization of Pro-growth Enhancers in Human Cancer Cells
Poshen B. Chen, Patrick C. Fiaux, Bin Li, Kai Zhang, Naoki Kubo, Shan Jiang, Rong Hu, Sihan Wu, Mengchi Wang, Wei Wang, Graham McVicker, Paul S. Mischel, Bing Ren
bioRxiv 2021.02.04.429675; doi: https://doi.org/10.1101/2021.02.04.429675
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Discovery and Functional Characterization of Pro-growth Enhancers in Human Cancer Cells
Poshen B. Chen, Patrick C. Fiaux, Bin Li, Kai Zhang, Naoki Kubo, Shan Jiang, Rong Hu, Sihan Wu, Mengchi Wang, Wei Wang, Graham McVicker, Paul S. Mischel, Bing Ren
bioRxiv 2021.02.04.429675; doi: https://doi.org/10.1101/2021.02.04.429675

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