Functional genomic approaches to elucidate the role of enhancers during development

Successful development depends on the precise tissue‐specific regulation of genes by enhancers, genetic elements that act as switches to control when and where genes are expressed. Because enhancers are critical for development, and the majority of disease‐associated mutations reside within enhancers, it is essential to understand which sequences within enhancers are important for function. Advances in sequencing technology have enabled the rapid generation of genomic data that predict putative active enhancers, but functionally validating these sequences at scale remains a fundamental challenge. Herein, we discuss the power of genome‐wide strategies used to identify candidate enhancers, and also highlight limitations and misconceptions that have arisen from these data. We discuss the use of massively parallel reporter assays to test enhancers for function at scale. We also review recent advances in our ability to study gene regulation during development, including CRISPR‐based tools to manipulate genomes and single‐cell transcriptomics to finely map gene expression. Finally, we look ahead to a synthesis of complementary genomic approaches that will advance our understanding of enhancer function during development. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease. Developmental Biology > Developmental Processes in Health and Disease. Laboratory Methods and Technologies > Genetic/Genomic Methods.