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Sanjana, N.E. et al. Science 353, 1545–1548 (2016).

The 98% of the human genome that does not encode proteins harbors many important regulatory regions, but identifying functions in such a vast genomic space is not trivial. Two research groups used CRISPR–Cas9-based screens to find regulatory elements in ∼1 megabase of the human genome. Sanjana et al. targeted Cas9 to regions around three genes involved in resistance to a BRAF inhibition in melanoma. They identified loci that determine transcription factor binding and the deposition of active or repressive histone modifications around one of the genes. Fulco et al. targeted dead Cas9 fused to a transcriptional inhibitor to the vicinity of two genes encoding transcription factors and found several enhancers that regulate gene expression. They observed the emergence of regulatory networks in which multiple enhancers regulate the same gene or where multiple genes are regulated by the same enhancer.