Research consortia have in recent years identified millions of DNA elements known as enhancers and promoters that are thought to regulate gene expression. But relatively few of these elements have been functionally defined, especially in cancer cells, where their dysregulation is known to play a central role in the genesis of tumors. In a November paper in Cell Reports, researchers led by Ludwig San Diego’s Bing Ren described their use of a CRISPR-based perturbation assay coupled with DNA sequencing to conduct a large-scale functional analysis of more than 11,000 putative enhancer elements required for cell proliferation and fitness—which they call essential enhancers—across ten human cancer cell lines. Aside from functionally validating hundreds of essential enhancers, their findings suggest that enhancers necessary for cell fitness typically adopt a modular structure. This structure is composed of activating elements enriched for DNA sequences recognized by transcription factors—proteins that regulate gene expression—that are known to be oncogenic surrounded by repressive elements that are enriched for sequences recognized by transcription factors that suppress tumor growth. Bing and his colleagues also showed, using data from clinical tumor samples, that the accessibility of chromatin harboring some essential enhancers is associated with patient survival.
Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation
Cell Reports, 2022 November 8