Enhancers in disease: molecular basis and emerging treatment strategies

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. HighlightsEnhancer disruption is increasingly implicated as a disease-driving mechanism. Chromosomal rearrangements can cause an enhancer to drive aberrant gene expression, genetic variants in enhancers can impact a transcription factor binding site, and disease-associated epigenetic changes are enriched in enhancer regions.The three big challenges in enhancer research focus on systematically identifying functional enhancers, their target genes, and the context in which they are active.Bromo-and extra-terminal (BET) inhibitors are a new class of drugs that target enhancers and inhibit gene expression. They are under investigation as treatment for cancer and other diseases.Gene editing techniques elucidate enhancer function and are being used to selectively regulate or mutate disturbed enhancers.

GRaNIE and GRaNPA: Inference and evaluation of enhancer-mediated gene regulatory networks applied to study macrophages

“…The strength of the eGRN framework is that we can specifically investigate the role of gene regulatory elements, such as enhancers, which are enriched for disease-associated genetic variants [1]. We therefore sought to explore the macrophage eGRNs to learn about gene regulatory mechanisms underlying associations of genetic variants with common complex traits and diseases.…”

“…Enhancers are genomic locations that play an important role in cell-type specific gene regulation, and an increasing number of diseases are linked to impaired enhancer function [1, 2]. This is particularly obvious for common genetic traits and diseases for which genome-wide association studies (GWAS) have linked over 200,000 genetic variants with over 40,000 traits and diseases, yet the vast majority of the disease-associated genetic variants lie in non-coding regions far from promoters [1], thus likely affecting enhancers and having a regulatory role.…”

Enhancer RNA Transcription Is Essential for a Novel CSF1 Enhancer in Triple-Negative Breast Cancer

“…Accumulated somatic mutations on top of these germline variants often have more profound effects, such as conferring growth advantages that drive tumor formation [ 126 , 127 ]. Additional mechanisms to activate oncogenes include chromosomal translocations that place them under the control of previously unassociated enhancers, large deletions or rearrangements that connect them with upregulating elements, amplifications that can convert an individual enhancer into a super-enhancer, and more discreet mutations that constitutively activate regulatory regions [ 33 , 128 , 129 ]. This emphasizes the need for expanded research into non-coding elements in the genome to fully understand the mechanisms of gene regulation and the consequences in cancer.…”

Epigenetics of alcohol-related liver diseases

“…Thus, identifying the role of one or a group of transcription factors in each cell type will help to identify new therapeutic targets, monitor responses, and provide insight into cell-cell interactions. Meanwhile, a lot of effort has also been put into the study of these pioneer transcription factors in cis-regulatory elements and E-P regulation, which are being recognised as druggable targets against disease onset and progression, 120 , 136 , 137 owing to their activity in a cell-identity and state-dependent manner. Advances in single-cell technologies will facilitate recognition of these interactions on a genome-wide level and provide new epigenomic target regions for known and novel genes of interest.…”