@article{0be9851cbb514f15a7f8cf7b8bb0da6a,
title = "Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation",
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",
author = "Chen, {Poshen B.} and Fiaux, {Patrick C.} and Kai Zhang and Bin Li and Naoki Kubo and Shan Jiang and Rong Hu and Emma Rooholfada and Sihan Wu and Mengchi Wang and Wei Wang and Graham McVicker and Mischel, {Paul S.} and Bing Ren",
note = "Funding Information: We thank H. Zhao for MYC reporter knockin constructs; J.S. Weissman for lenti-KRAB-dCas9-BFP plasmid; C.A. Gersbach for lenti-KRAB-dCas9-sgRNA vector; A. Stark for hSTARR_ORI plasmid; and G. Li, Q. Zhu, M. Tastemel, and all members of the Ren lab for many productive and exciting discussions of this work. S.W. is supported by the Cancer Prevention and Research Institute of Texas (no. RR210034). The work is supported by NIH ( UM1 HG009402 , to B.R.) and the Ludwig Institute for Cancer Research . Funding Information: We thank H. Zhao for MYC reporter knockin constructs; J.S. Weissman for lenti-KRAB-dCas9-BFP plasmid; C.A. Gersbach for lenti-KRAB-dCas9-sgRNA vector; A. Stark for hSTARR_ORI plasmid; and G. Li, Q. Zhu, M. Tastemel, and all members of the Ren lab for many productive and exciting discussions of this work. S.W. is supported by the Cancer Prevention and Research Institute of Texas (no. RR210034). The work is supported by NIH (UM1 HG009402, to B.R.) and the Ludwig Institute for Cancer Research. P.B.C. S.W. P.S.M. and B.R. designed the study. P.B.C. R.H. and E.R. carried out the experiments. P.B.C. and B.L. developed computational methods to design paired sgRNAs for genome-wide screening. P.B.C. B.L. P.C.F. K.Z. N.K. S.J. M.W. W.W. G.M. and B.R. contributed to data analysis and interpretation. P.B.C. P.C.F. K.Z. S.J. and B.R. wrote the manuscript with input from all authors. B.R. supervised the work and obtained funding. B.R. is a co-founder and consultant of Arima Genomics, Inc. and co-founder of Epigenome Technologies, Inc.; and P.S.M. is a co-founder and consultant of Boundless Bio, Inc. He has equity in the company and chairs the scientific advisory board, for which he is compensated. S.W. is a member of the scientific advisory board of Dimension Genomics Inc. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = nov,
day = "8",
doi = "10.1016/j.celrep.2022.111630",
language = "English (US)",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}