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

Cell Rep

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:

Published: November 2022

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687083PMC
http://dx.doi.org/10.1016/j.celrep.2022.111630DOI Listing

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