Abstract
Enhancers are genomic sequences that play a key role in regulating tissue-specific gene expression levels. An increasing number of diseases are linked to impaired enhancer function through chromosomal rearrangement, genetic variation within enhancers, or epigenetic modulation. Here, we review how these enhancer disruptions have recently been implicated in congenital disorders, cancers, and common complex diseases and address the implications for diagnosis and treatment. Although further fundamental research into enhancer function, target genes, and context is required, enhancer-targeting drugs and gene editing approaches show great therapeutic promise for a range of diseases.
Highlights
Enhancers and their role in human disease Gene expression is regulated by numerous factors, including polymerase recruitment, epigenetic signaling, and transcription factors (TFs) that regulate the activity of gene promoters and enhancers
With the advent of genome-wide association studies (GWAS) that identify associations between genetic variants and complex traits and diseases, it became clear that the majority of trait-linked genetic variants lie in noncoding genomic regions far from promoters, likely targeting enhancers
It may not be surprising that prioritization of known disease genes by local Expression quantitative trait locus (eQTL) colocalization does not outperform taking the gene with the closest transcription start site to the GWAS variant [18,29]
Summary
A recent analysis of whole-genome sequencing profiles in over 1200 cancer genomes found hundreds of genes for which expression alterations were observed within 100 kb of a structural variation breakpoint, some of which could be attributed to enhancer hijacking [10] These data indicate that enhancer hijacking may be a more common mechanism in cancer than we currently appreciate based on the few validated examples. While a large number of disease-related copy number variations (CNVs) are predicted to affect TAD structure [14,15], a whole-genome analysis in over 2500 cancer genomes identified almost 300 000 TAD disruptions, of which only 14% led to a change in gene expression [16].
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