Decoding the noncoding genome via large-scale CRISPR screens

Large portions of the human genome harbor functional noncoding elements, which can regulate a variety of biological processes and have important implications for disease risk and therapeutic outcomes. However, assigning specific functions to noncoding sequences remains a major challenge. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein (Cas) systems have emerged as a powerful approach for targeted genome and epigenome perturbation. CRISPR systems are now harnessed for high-throughput screening of the noncoding genome to uncover functional regulatory elements and to define their precise functions with superior speed. Here, we summarize the various tools developed for such screens in mammalian systems and discuss screening methods and technical considerations. We further highlight screens that are already transforming our understanding of gene regulation and disease mechanisms, consider the impact of such discoveries on the development of new therapeutics, and provide our viewpoint on the challenges for future development of the field.