Journal
SCIENCE
Volume 353, Issue 6307, Pages 1545-1549Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaf7613
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Funding
- NIH from the National Human Genome Research Institute [R00-HG008171]
- Simons Center for the Social Brain at the Massachusetts Institute of Technology
- NIH [F32-DK096822]
- NIH through the National Institute of Mental Health [5DP1-MH100706, 1R01-MH110049]
- NSF
- New York Stem Cell, Simons, Paul G. Allen Family, and Vallee Foundations
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The noncoding genome affects gene regulation and disease, yet we lack tools for rapid identification and manipulation of noncoding elements. We developed a CRISPR screen using similar to 18,000 single guide RNAs targeting >700 kilobases surrounding the genes NF1, NF2, and CUL3, which are involved in BRAF inhibitor resistance in melanoma. We find that noncoding locations that modulate drug resistance also harbor predictive hallmarks of noncoding function. With a subset of regions at the CUL3 locus, we demonstrate that engineered mutations alter transcription factor occupancy and long-range and local epigenetic environments, implicating these sites in gene regulation and chemotherapeutic resistance. Through our expansion of the potential of pooled CRISPR screens, we provide tools for genomic discovery and for elucidating biologically relevant mechanisms of gene regulation.
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