Enhancers in disease: molecular basis and emerging treatment strategies
Authors: Annique Claringbould, Judith B. Zaugg
Journal: Trends in Molecular Medicine (2021)

Enhancer 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. 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. 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. Gene expression is regulated by numerous factors, including polymerase recruitment, epigenetic signaling, and transcription factors (TFs) (see Glossary) that regulate the activity of gene promoters and enhancers. Enhancers are regulatory sequences in the genome that affect gene expression of a nearby gene. The exact definition of enhancers and the mechanism by which they regulate gene expression is still a matter of active research (Box 1). The current view is that they act by recruiting specific TFs and polymerase to a distal site, which then activate gene expression through a mechanism that involves physical contact with the gene promoter (Figure 1A ). More recently, it has been proposed that enhancers can form highly active genomic clusters (super enhancers or stretch enhancers [1.Pott S. Lieb J.D. What are super-enhancers?.Nat. Genet. 2015; 47: 8-12Crossref PubMed Scopus (330) Google Scholar]), which may act in a phase-separated assembly of molecules [2.Hnisz D. et al.A phase separation model for transcriptional control.Cell. 2017; 169: 13-23Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar].Box 1Enhancer features, function, and identificationEnhancers can regulate gene expression by recruiting TFs and the transcriptional machinery and subsequently forming a loop with the promoter region of the target gene (see Figure 1A in main text) [87.Spitz F. Furlong E.E.M. Transcription factors: from enhancer binding to developmental control.Nat. Rev. Genet. 2012; 13: 613-626Crossref PubMed Scopus (961) Google Scholar]. Chromatin is spatially organized into large domains called TADs, which comprise smaller loops, including enhancer–promoter loops [88.Dixon J.R. et al.Topological domains in mammalian genomes identified by analysis of chromatin interactions.Nature. 2012; 485: 376-380Crossref PubMed Scopus (3314) Google Scholar, 89.Krijger P.H.L. de Laat W. Regulation of disease-associated gene expression in the 3D genome.Nat. Rev. Mol. Cell Biol. 2016; 17: 771-782Crossref PubMed Scopus (124) Google Scholar, 90.Nora E.P. et al.Spatial partitioning of the regulatory landscape of the X-inactivation centre.Nature. 2012; 485: 381-385Crossref PubMed Scopus (1527) Google Scholar, 91.Rao S.S.P. et al.A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.Cell. 2014; 159: 1665-1680Abstract Full Text Full Text PDF PubMed Scopus (2775) Google Scholar]. The cohesin complex demarcates TAD boundaries and forms smaller enhancer–promoter loops by active extrusion of chromatin through its ring-shaped structure [92.Rao S.S.P. et al.Cohesin loss eliminates all loop domains.Cell. 2017; 171: 305-320Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar,93.Schwarzer W. et al.Two independent modes of chromatin organization revealed by cohesin removal.Nature. 2017; 551: 51-56Crossref PubMed Scopus (426) Google Scholar]. Chromatin looping allows enhancers to target distal genes, although most target genes are located nearby on the linear chromosome [94.Furlong E.E.M. Levine M. Developmental enhancers and chromosome topology.Science. 2018; 361: 1341-1345Crossref PubMed Scopus (168) Google Scholar]. The effect of chromatin organization on gene expression is still under debate, as reviewed in [89.Krijger P.H.L. de Laat W. Regulation of disease-associated gene expression in the 3D genome.Nat. Rev. Mol. Cell Biol. 2016; 17: 771-782Crossref PubMed Scopus (124) Google Scholar,95.Ruiz-Velasco M. Zaugg J.B. Structure meets function: how chromatin organisation conveys functionality.Curr. Opin. Syst. Biol. 2017; 1: 129-136Crossref Google Scholar]. On the one hand, cohesin-mediated enhancer–promoter loops across cell lines correlate with gene expression [96.Grubert F. et al.Landscape of cohesin-mediated chromatin loops in the human genome.Nature. 2020; 583: 737-743Crossref PubMed Scopus (23) Google Scholar] and mutations to the cohesin complex result in loss of gene expression [97.Liu N.Q. et al.WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation.Nat. Genet. 2021; 53: 100-109Crossref PubMed Scopus (13) Google Scholar]. On the other hand, multiple studies have shown that changes in TAD organization do not translate to changes in gene expression [98.Ghavi-Helm Y. et al.Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression.Nat. Genet. 2019; 51: 1272-1282Crossref PubMed Scopus (97) Google Scholar,99.Ing-Simmons E. et al.Independence of 3D chromatin conformation and gene regulation during Drosophila dorsoventral patterning.Nat. Genet. 2021; 53: 487-499Crossref PubMed Scopus (0) Google Scholar].An enhancer sequence can be validated experimentally by measuring its ability to drive expression of a reporter gene on a plasmid [100.Arnold C.D. et al.Genome-wide quantitative enhancer activity maps identified by STARR-seq.Science. 2013; 339: 1074-1077Crossref PubMed Scopus (477) Google Scholar] or inserted into the genome [101.Inoue F. et al.A systematic comparison reveals substantial differences in chromosomal versus episomal encoding of enhancer activity.Genome Res. 2017; 27: 38-52Crossref PubMed Scopus (100) Google Scholar]. However, it is challenging to investigate enhancer activity in their endogenous locus. Recent advances in CRISPR methods have started to address this by inducing or repressing specific enhancer elements in endogenous loci [41.Schraivogel D. et al.Targeted Perturb-seq enables genome-scale genetic screens in single cells.Nat. Methods. 2020; 17: 629-635Crossref PubMed Scopus (17) Google Scholar,42.Dixit A. et al.Perturb-seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens.Cell. 2016; 167: 1853-1866Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar,102.Fulco C.P. et al.Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations.Nat. Genet. 2019; 51: 1664-1669Crossref PubMed Scopus (110) Google Scholar] and measuring gene expression. A complementary approach is to predict endogenous enhancers based on their biochemical properties. Enhancers are characterized by specific chromatin modifications like H3K4me1 and H3K27ac [103.Spicuglia S. Vanhille L. Chromatin signatures of active enhancers.Nucleus. 2012; 3: 126-131Crossref PubMed Google Scholar, 104.Ong C.-T. Corces V.G. Enhancer function: new insights into the regulation of tissue-specific gene expression.Nat. Rev. Genet. 2011; 12: 283-293Crossref PubMed Scopus (533) Google Scholar, 105.Ernst J. Kellis M. ChromHMM: automating chromatin-state discovery and characterization.Nat. Methods. 2012; 9: 215-216Crossref PubMed Scopus (1098) Google Scholar]. Active enhancers are often flanked by bidirectional capped RNAs, indicating that they can activate transcription both upstream and downstream [84.Andersson R. et al.An atlas of active enhancers across human cell types and tissues.Nature. 2014; 507: 455-461Crossref PubMed Scopus (1282) Google Scholar,106.Kim T.-K. et al.Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers.Cold Spring Harb. Perspect. Biol. 2015; 7a018622Crossref PubMed Scopus (82) Google Scholar].Enhancers can form highly active genomic clusters (super enhancers or stretch enhancers [1.Pott S. Lieb J.D. What are super-enhancers?.Nat. Genet. 2015; 47: 8-12Crossref PubMed Scopus (330) Google Scholar]) with a shared function in cell type-specific gene regulation, although it is not yet clear if the individual enhancers each play a separate role or whether they are mostly redundant [107.Miguel-Escalada I. et al.Transcriptional enhancers: functional insights and role in human disease.Curr. Opin. Genet. Dev. 2015; 33: 71-76Crossref PubMed Scopus (16) Google Scholar,108.Bravo González-Blas C. et al.Identification of genomic enhancers through spatial integration of single-cell transcriptomics and epigenomics.Mol. Syst. Biol. 2020; 16e9438Crossref PubMed Scopus (12) Google Scholar]. Super enhancers seem particularly vulnerable to the loss of chromatin structure, for example, by downregulating cohesin and disturbing chromatin organization [92.Rao S.S.P. et al.Cohesin loss eliminates all loop domains.Cell. 2017; 171: 305-320Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar]. Enhancer clusters may act in a phase-separated assembly of molecules [2.Hnisz D. et al.A phase separation model for transcriptional control.Cell. 2017; 169: 13-23Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar]: modifications of TFs, enhancer sequences, and other regulatory factors form temporary links that result in a phase-separated multi-molecular complex of transcriptional regulators that drives cooperativity within a super enhancer [2.Hnisz D. et al.A phase separation model for transcriptional control.Cell. 2017; 169: 13-23Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar,109.Boija A. et al.Transcription factors activate genes through the phase-separation capacity of their activation domains.Cell. 2018; 175: 1842-1855Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar]. Enhancers can regulate gene expression by recruiting TFs and the transcriptional machinery and subsequently forming a loop with the promoter region of the target gene (see Figure 1A in main text) [87.Spitz F. Furlong E.E.M. Transcription factors: from enhancer binding to developmental control.Nat. Rev. Genet. 2012; 13: 613-626Crossref PubMed Scopus (961) Google Scholar]. Chromatin is spatially organized into large domains called TADs, which comprise smaller loops, including enhancer–promoter loops [88.Dixon J.R. et al.Topological domains in mammalian genomes identified by analysis of chromatin interactions.Nature. 2012; 485: 376-380Crossref PubMed Scopus (3314) Google Scholar, 89.Krijger P.H.L. de Laat W. Regulation of disease-associated gene expression in the 3D genome.Nat. Rev. Mol. Cell Biol. 2016; 17: 771-782Crossref PubMed Scopus (124) Google Scholar, 90.Nora E.P. et al.Spatial partitioning of the regulatory landscape of the X-inactivation centre.Nature. 2012; 485: 381-385Crossref PubMed Scopus (1527) Google Scholar, 91.Rao S.S.P. et al.A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.Cell. 2014; 159: 1665-1680Abstract Full Text Full Text PDF PubMed Scopus (2775) Google Scholar]. The cohesin complex demarcates TAD boundaries and forms smaller enhancer–promoter loops by active extrusion of chromatin through its ring-shaped structure [92.Rao S.S.P. et al.Cohesin loss eliminates all loop domains.Cell. 2017; 171: 305-320Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar,93.Schwarzer W. et al.Two independent modes of chromatin organization revealed by cohesin removal.Nature. 2017; 551: 51-56Crossref PubMed Scopus (426) Google Scholar]. Chromatin looping allows enhancers to target distal genes, although most target genes are located nearby on the linear chromosome [94.Furlong E.E.M. Levine M. Developmental enhancers and chromosome topology.Science. 2018; 361: 1341-1345Crossref PubMed Scopus (168) Google Scholar]. The effect of chromatin organization on gene expression is still under debate, as reviewed in [89.Krijger P.H.L. de Laat W. Regulation of disease-associated gene expression in the 3D genome.Nat. Rev. Mol. Cell Biol. 2016; 17: 771-782Crossref PubMed Scopus (124) Google Scholar,95.Ruiz-Velasco M. Zaugg J.B. Structure meets function: how chromatin organisation conveys functionality.Curr. Opin. Syst. Biol. 2017; 1: 129-136Crossref Google Scholar]. On the one hand, cohesin-mediated enhancer–promoter loops across cell lines correlate with gene expression [96.Grubert F. et al.Landscape of cohesin-mediated chromatin loops in the human genome.Nature. 2020; 583: 737-743Crossref PubMed Scopus (23) Google Scholar] and mutations to the cohesin complex result in loss of gene expression [97.Liu N.Q. et al.WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation.Nat. Genet. 2021; 53: 100-109Crossref PubMed Scopus (13) Google Scholar]. On the other hand, multiple studies have shown that changes in TAD organization do not translate to changes in gene expression [98.Ghavi-Helm Y. et al.Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression.Nat. Genet. 2019; 51: 1272-1282Crossref PubMed Scopus (97) Google Scholar,99.Ing-Simmons E. et al.Independence of 3D chromatin conformation and gene regulation during Drosophila dorsoventral patterning.Nat. Genet. 2021; 53: 487-499Crossref PubMed Scopus (0) Google Scholar]. An enhancer sequence can be validated experimentally by measuring its ability to drive expression of a reporter gene on a plasmid [100.Arnold C.D. et al.Genome-wide quantitative enhancer activity maps identified by STARR-seq.Science. 2013; 339: 1074-1077Crossref PubMed Scopus (477) Google Scholar] or inserted into the genome [101.Inoue F. et al.A systematic comparison reveals substantial differences in chromosomal versus episomal encoding of enhancer activity.Genome Res. 2017; 27: 38-52Crossref PubMed Scopus (100) Google Scholar]. However, it is challenging to investigate enhancer activity in their endogenous locus. Recent advances in CRISPR methods have started to address this by inducing or repressing specific enhancer elements in endogenous loci [41.Schraivogel D. et al.Targeted Perturb-seq enables genome-scale genetic screens in single cells.Nat. Methods. 2020; 17: 629-635Crossref PubMed Scopus (17) Google Scholar,42.Dixit A. et al.Perturb-seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens.Cell. 2016; 167: 1853-1866Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar,102.Fulco C.P. et al.Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations.Nat. Genet. 2019; 51: 1664-1669Crossref PubMed Scopus (110) Google Scholar] and measuring gene expression. A complementary approach is to predict endogenous enhancers based on their biochemical properties. Enhancers are characterized by specific chromatin modifications like H3K4me1 and H3K27ac [103.Spicuglia S. Vanhille L. Chromatin signatures of active enhancers.Nucleus. 2012; 3: 126-131Crossref PubMed Google Scholar, 104.Ong C.-T. Corces V.G. Enhancer function: new insights into the regulation of tissue-specific gene expression.Nat. Rev. Genet. 2011; 12: 283-293Crossref PubMed Scopus (533) Google Scholar, 105.Ernst J. Kellis M. ChromHMM: automating chromatin-state discovery and characterization.Nat. Methods. 2012; 9: 215-216Crossref PubMed Scopus (1098) Google Scholar]. Active enhancers are often flanked by bidirectional capped RNAs, indicating that they can activate transcription both upstream and downstream [84.Andersson R. et al.An atlas of active enhancers across human cell types and tissues.Nature. 2014; 507: 455-461Crossref PubMed Scopus (1282) Google Scholar,106.Kim T.-K. et al.Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers.Cold Spring Harb. Perspect. Biol. 2015; 7a018622Crossref PubMed Scopus (82) Google Scholar]. Enhancers can form highly active genomic clusters (super enhancers or stretch enhancers [1.Pott S. Lieb J.D. What are super-enhancers?.Nat. Genet. 2015; 47: 8-12Crossref PubMed Scopus (330) Google Scholar]) with a shared function in cell type-specific gene regulation, although it is not yet clear if the individual enhancers each play a separate role or whether they are mostly redundant [107.Miguel-Escalada I. et al.Transcriptional enhancers: functional insights and role in human disease.Curr. Opin. Genet. Dev. 2015; 33: 71-76Crossref PubMed Scopus (16) Google Scholar,108.Bravo González-Blas C. et al.Identification of genomic enhancers through spatial integration of single-cell transcriptomics and epigenomics.Mol. Syst. Biol. 2020; 16e9438Crossref PubMed Scopus (12) Google Scholar]. Super enhancers seem particularly vulnerable to the loss of chromatin structure, for example, by downregulating cohesin and disturbing chromatin organization [92.Rao S.S.P. et al.Cohesin loss eliminates all loop domains.Cell. 2017; 171: 305-320Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar]. Enhancer clusters may act in a phase-separated assembly of molecules [2.Hnisz D. et al.A phase separation model for transcriptional control.Cell. 2017; 169: 13-23Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar]: modifications of TFs, enhancer sequences, and other regulatory factors form temporary links that result in a phase-separated multi-molecular complex of transcriptional regulators that drives cooperativity within a super enhancer [2.Hnisz D. et al.A phase separation model for transcriptional control.Cell. 2017; 169: 13-23Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar,109.Boija A. et al.Transcription factors activate genes through the phase-separation capacity of their activation domains.Cell. 2018; 175: 1842-1855Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar]. Shortly after the first enhancer sequence was described to affect the expression of a rabbit hemoglobin β-1 gene [3.Banerji J. et al.Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences.Cell. 1981; 27: 299-308Abstract Full Text PDF PubMed Scopus (849) Google Scholar], evidence that enhancer disruption could lead to disease in humans was found, with the misregulation of the human β-globin gene by a DNA translocation in patients suffering from β-thalassemia [4.Kioussis D. et al.β-Globin gene inactivation by DNA translocation in γβ-thalassaemi.Nature. 1983; 306: 662-666Crossref PubMed Scopus (0) Google Scholar]. Since then, a number of other enhanceropathies have been identified [5.Smith E. Shilatifard A. Enhancer biology and enhanceropathies.Nat. Struct. Mol. Biol. 2014; 21: 210-219Crossref PubMed Scopus (162) Google Scholar], including polydactyly caused by mutations 1 Mb away from the Sonic hedgehog gene [6.Lettice L.A. et al.Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 7548-7553Crossref PubMed Scopus (0) Google Scholar] and the translocation of the IgH enhancer resulting in overexpression of MYC in Burkitt's lymphoma [7.Taub R. et al.Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells.Proc. Natl. Acad. Sci. U. S. A. 1982; 79: 7837-7841Crossref PubMed Scopus (0) Google Scholar]. 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, thus likely targeting enhancers. These associations, together with an increasing number of enhancer-mediated mechanisms driving cancer and rare diseases, suggest that enhancers are on the way to becoming the next big frontier in drug target identification. Structural variation may induce 'enhancer hijacking' if an active enhancer is misplaced such that it regulates genes that are not their original targets [8.Northcott P.A. et al.Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.Nature. 2014; 511: 428-434Crossref PubMed Scopus (312) Google Scholar]. This phenomenon has been described in cancer, where enhancers can be misplaced through chromosomal rearrangements [8.Northcott P.A. et al.Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.Nature. 2014; 511: 428-434Crossref PubMed Scopus (312) Google Scholar] or micro-amplification of genomic regions [9.Abraham B.J. et al.Small genomic insertions form enhancers that misregulate oncogenes.Nat. Commun. 2017; 8: 14385Crossref PubMed Scopus (38) Google Scholar], to induce the expression of an oncogene (Table 1). 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.Zhang Y. et al.High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.Nat. Commun. 2020; 11: 736Crossref PubMed Scopus (21) Google Scholar]. These data indicate that enhancer hijacking may be a more common mechanism in cancer than we currently appreciate based on the few validated examples. Yet the dual challenge of identifying functional enhancers and determining the cancer-driving potential of mutations makes this phenomenon particularly hard to study.Table 1Examples of enhancer disruptions driving diseaseaAbbreviations: CCNE1, cyclin E1; CpG, cytosine and guanine nucleotide sequence; CSMD1, CUB and Sushi Multiple Domains 1; CTCF, CCCTC-binding factor; FMR1, Fragile X Mental Retardation Protein 1; GFI1, Growth Factor Independent 1; GWAS, genome-wide association study; HOXA, Homeobox A; IGF2, insulin-like Growth Factor 2; LMO2, LIM Domain Only 2; MEF2C, Myocyte Enhancer Factor 2C; PTF1A, Pancreas Associated Transcription Factor 1A; RASGRP1, RAS Guanyl Releasing Protein 1; RET, Ret Proto-Oncogene; SNP, single nucleotide polymorphism; SOX9, SRY-Box Transcription Factor 9; TAD, topologically associated domain; TBX5, T-Box Transcription Factor 5; TF, transcription factor; ZBTB16, Zinc Finger And BTB Domain Containing 16.Disruption mechanismPhenotypeDescriptionRefsEnhancer hijackingMedulloblastomaSomatic genomic rearrangements result in a fusion of an active enhancer with oncogenes GFI1 or GFI1B[8.Northcott P.A. et al.Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.Nature. 2014; 511: 428-434Crossref PubMed Scopus (312) Google Scholar]Enhancer hijacking(Pediatric) cancersAmplification of MYCN can be regulated by local and distal enhancers[113.Helmsauer K. et al.Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma.Nat. Commun. 2020; 11: 5823Crossref PubMed Scopus (7) Google Scholar]Enhancer hijackingSalivary gland acinic cell carcinomaRearrangements translocate active enhancer to activate NR4A3, a TF that then upregulates its target genes[114.Haller F. et al.Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands.Nat. Commun. 2019; 10: 368Crossref PubMed Scopus (61) Google Scholar]Enhancer hijackingMultiple cancers18 candidate enhancer hijacking events in a pan-cancer analysis and 98 in tumor-type specific analyses (including IGF2 in colorectal cancer)[115.Weischenfeldt J. et al.Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.Nat. Genet. 2017; 49: 65-74Crossref PubMed Scopus (170) Google Scholar]Enhancer hijackingPrimary gastric adenocarcinomaRearrangements lead to enhancers mistargeting CCNE1 and IGF2[116.Ooi W.F. et al.Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma.Gut. 2020; 69: 1039-1052Crossref PubMed Scopus (9) Google Scholar]Enhancer hijackingT-lineage acute lymphoblastic leukaemiaTranslocations lead to enhancer hijacking of the HOXA gene cluster[117.Yang L. et al.3D genome analysis identifies enhancer hijacking mechanism for high-risk factors in human T-lineage acute lymphoblastic leukemia.BioRxiv. 2020; (Published online Mach 12, 2020)https://doi.org/10.1101/2020.03.11.988279Google Scholar]Enhancer hijackingT-lineage acute lymphoblastic leukemiaSmall insertions in the enhancers that regulate oncogenes (e.g. LMO2) drive aberrant expression[9.Abraham B.J. et al.Small genomic insertions form enhancers that misregulate oncogenes.Nat. Commun. 2017; 8: 14385Crossref PubMed Scopus (38) Google Scholar]TAD boundary removalLimb malformationsTAD boundary removed by rearrangements, subsequent fusion of two TADs, enhancer Epha4 regulates genes in both domains leading to ectopic expression[12.Lupiáñez D.G. et al.Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.Cell. 2015; 161: 1012-1025Abstract Full Text Full Text PDF PubMed Scopus (941) Google Scholar]TAD boundary removal5q14.3 microdeletion syndromeDisrupted TAD structure in patients leads to decreased expression of MEF2C, a known disease gene[118.Redin C. et al.The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.Nat. Genet. 2017; 49: 36-45Crossref PubMed Google Scholar]TAD boundary removalFragile X syndromeCTCF binding impaired by CGG triplet repeat near FMR1[13.Sun J.H. et al.Disease-associated short tandem repeats co-localize with chromatin domain boundaries.Cell. 2018; 175: 224-238Abstract Full Text Full Text PDF PubMed Google Scholar]Mutation in enhancerPierre Robin syndromeMicrodeletion in a developmental enhancer that regulates SOX9 in the nervous system and skeletal structures[119.Benko S. et al.Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.Nat. Genet. 2009; 41: 359-364Crossref PubMed Scopus (266) Google Scholar]Mutation in enhancerIsolated atrial defectsHomozygous point mutation located in a highly conserved enhancer region 90 kb downstream of the developmental transcription factor TBX5[120.Smemo S. et al.Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease.Hum. Mol. Genet. 2012; 21: 3255-3263Crossref PubMed Scopus (117) Google Scholar]Mutation in enhancerIsolated pancreatic agenesisMutations within PTF1A enhancer[121.Weedon M.N. et al.Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.Nat. Genet. 2014; 46: 61-64Crossref PubMed Scopus (166) Google Scholar]Mutation in enhancerIntellectual disabilityEnrichment of de novo mutations in fetal brain-specific enhancers, identification of enhancer that regulates CSMD1 and affects neurogenesis[21.De Vas M.G. et al.De novo mutations in fetal brain specific enhancers play a significant role in severe intellectual disability.BioRxiv. 2019; (Published online April 28, 2019)https://doi.org/10.1101/621029Google Scholar]Enrichment of SNPs in enhancersCrohn's disease, multiple sclerosis, electrocardiogram phenotypesCell type-specific enrichment of GWAS SNPs in DNase I hypersensitivity sites of Th17, CD3+, and heart cell, respectively[122.Maurano M.T. et al.Systematic localization of common disease-associated variation in regulatory DNA.Science. 2012; 337: 1190-1195Crossref PubMed Scopus (1901) Google Scholar]Enrichment of SNPs in enhancersImmune diseases60% of GWAS fine-mapped variants located in immune cell enhancers[123.Farh K.K-H. et al.Genetic and epigenetic fine mapping of causal autoimmune disease variants.Nature. 2015; 518: 337-343Crossref PubMed Scopus (964) Google Scholar]Enrichment of SNPs in enhancersType I diabetesGWAS SNPs enriched in thymus, CD4+ and CD8+ T cells, B cells, and CD34+ enhancers[124.Onengut-Gumuscu S. et al.Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.Nat. Genet. 2015; 47: 381-386Crossref PubMed Scopus (317) Google Scholar]Enrichment of SNPs in enhancersType II diabetesGWAS SNPs enriched in pancreatic islet enhancer regions[125.Pasquali L. et al.Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants.Nat. Genet. 2014; 46: 136-143Crossref PubMed Scopus (303) Google Scholar]Enrichment of SNPs in enhancersImmunodeficiencyTwo enhancers influencing RASGRP1 levels enriched for autoimmunity-associated SNPs[126.Baars M.J.D. et