Epigenetics & Chromatin

Introduction: Acquirement of somatic mutations (SMs) in the genome is the driving force of cancer. To date, most research on the functional signifi cance of SMs was focused on the discovery of cancer-driving alterations in protein-coding sequences. However, the protein-coding exome comprises less than 3% of the human genome. Emerging evidence indicate a previously unappreciated role for cancer-driving noncoding SMs that alter the activity

of regulatory elements that control the expression of tumor suppressors or oncogenes.

Methods: Th e maturation of the CRISPR-Cas9 genome-editing technology revolutionizes our ability to study the function of noncoding elements. We harness this technology to study the noncoding genome, and recently performed the first wide-scale CRISPR-based functional genomic screen that systematically targets enhancer elements in the

human genome.

Results: Our proof-of-principle screens focused on two transcription factors (TFs), p53 and ERα, which play key roles in cancer initiation and progression, and identifi ed enhancers that are critical for the function of these regulators. Our follow-up screens are signifi cantly expanding the scope of the initial ones, and, based on various epigenomic techniques and the CRISPR-Cas9 tool, target regulatory elements that are bound by multiple cancerrelated

TFs. Th ese studies further discovered novel enhancers that mediate oncogenic and tumor-suppressive effects, and mapped the target genes that are regulated by these elements.

Conclusion: As exome-sequencing becomes a central tool for precision oncology, our results pinpoint critical genomic elements that go beyond coding sequences and should be prioritized too for clinical sequencing, to improve our understanding of the mutational processes that drive each tumor and thus potentially guide a better treatment.