Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation

Poshen B Chen; Patrick C Fiaux; Kai Zhang; Bin Li; Naoki Kubo; Shan Jiang; Rong Hu; Emma Rooholfada; Sihan Wu; Mengchi Wang; Wei Wang; Graham McVicker; Paul S Mischel; Bing Ren

doi:10.1016/j.celrep.2022.111630

Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation

Cell Rep. 2022 Nov 8;41(6):111630. doi: 10.1016/j.celrep.2022.111630.

Authors

Poshen B Chen¹, Patrick C Fiaux², Kai Zhang³, Bin Li³, Naoki Kubo³, Shan Jiang³, Rong Hu³, Emma Rooholfada³, Sihan Wu⁴, Mengchi Wang², Wei Wang⁵, Graham McVicker⁶, Paul S Mischel⁷, Bing Ren⁸

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore 138672, Singapore.
² Bioinformatics and System Biology Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA.
³ Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
⁴ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
⁵ Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Bioinformatics and System Biology Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA.
⁶ Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁷ Department of Pathology, Stanford Medicine, Stanford University, Stanford, CA 94305, USA; ChEM-H, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA; Institute of Genome Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA; Ludwig Institute for Cancer Research, San Diego, La Jolla, CA 92093, USA. Electronic address: biren@ucsd.edu.

Abstract

A scarcity of functionally validated enhancers in the human genome presents a significant hurdle to understanding how these cis-regulatory elements contribute to human diseases. We carry out highly multiplexed CRISPR-based perturbation and sequencing to identify enhancers required for cell proliferation and fitness in 10 human cancer cell lines. Our results suggest that the cell fitness enhancers, unlike their target genes, display high cell-type specificity of chromatin features. They typically adopt a modular structure, comprised of activating elements enriched for motifs of oncogenic transcription factors, surrounded by repressive elements enriched for motifs recognized by transcription factors with tumor suppressor functions. We further identify cell fitness enhancers that are selectively accessible in clinical tumor samples, and the levels of chromatin accessibility are associated with patient survival. These results reveal functional enhancers across multiple cancer cell lines, characterize their context-dependent chromatin organization, and yield insights into altered transcription programs in cancer cells.

Keywords: CP: Cancer; CP: Molecular biology; cell proliferation; functional enhancer; gene regulation; oncogene.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cell Proliferation / genetics
Chromatin
Enhancer Elements, Genetic* / genetics
Genome, Human
Humans
Neoplasms* / genetics
Transcription Factors / metabolism

Substances

Chromatin
Transcription Factors

Grants and funding

UM1 HG009402/HG/NHGRI NIH HHS/United States