Enhancers in Development and Diseases

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This entry is adapted from the peer-reviewed paper 10.3390/epigenomes5040021

Enhancers are cis-regulatory elements containing short DNA sequences that serve as binding sites for pioneer/regulatory transcription factors, thus orchestrating the regulation of genes critical for lineage determination. The activity of enhancer elements is believed to be determined by transcription factor binding, thus determining the cell state identity during development. Precise spatio-temporal control of the transcriptome during lineage specification requires the coordinated binding of lineage-specific transcription factors to enhancers. Thus, enhancers are the primary determinants of cell identity. Numerous studies have explored the role and mechanism of enhancers during development and disease, and various basic questions related to the functions and mechanisms of enhancers have not yet been fully answered.

enhancer poised cis-regulatory lineage spatio-temporal

1. Introduction

The term “enhancer” was first coined based on studies of Simian virus 40 (SV40) when, in 1981, Banerji et al. observed for the first time that a viral DNA element from SV40 had the ability to enhance activity towards a T-antigen or β-globin reporter in mammalian cells ^[1]. Further research has explored endogenous sequences with similar functions in the immunoglobulin heavy chain locus. These preliminary studies have established that enhancers function as short DNA elements that trigger a gene’s transcription from a long distance in an orientation-independent manner. Preliminary studies have determined the exact mechanism of how distal regulatory elements regulate gene transcription through distal enhancers ^[2]. Enhancers are cis-regulatory elements that carry epigenetic information in DNA sequences through specific histone modifications ^[3]. Studies assessing the characteristics of enhancers have reported that they can function independently of the orientation and distance to their cognate target genes, at distances sometimes of several hundred kilobases or megabases ^[2]^[4]^[5]. Enhancers can be identified and characterized by various factors, including histone modifications, their transcription into non-coding RNAs, and their epigenetic features ^[6]. The prominent feature of enhancers is their ability to serve as a docking platform for transcription factor binding, where developmental signaling (intrinsic or extrinsic) cues are interpreted in a highly context-specific manner ^[7]. The signatures of these enhancers are highly cell type-specific; such cell type-specific use of the epigenetic information has demonstrated the combinatorial function of transcription factors in maintaining cell identity and lineage determination ^[8]. The cell type-specific enhancer pattern provides a unique cis-regulatory platform, in which transcription factors are activated by developmental cues and modify the transcriptome ^[9]^[10]^[11]. This model revealed that every developmental stage has a cell type-specific transcription factor, which functions by cell type-specific enhancer signatures ^[12]. Enhancers are actuated in a stage-specific manner, correlated with cell type-specific histone modifications. This combinatorial mechanism of transcription factor binding on cell type-specific enhancers results in the so-called enhancer signature, which serves as a readout to define enhancers in a cell type-specific manner at a global scale ^[13]. Precise spatial and temporal control of gene expression and the correct interpretation of the enhancer signature are crucial in the development process. Any alterations in the enhancer signature can modify the gene expression pattern and ethe capacity of the enhancer to respond to developmental signals, narrowing cell differentiation and affecting correct lineage formation. Heinz et al. (2010) have shown that lineage-determining transcription factors bind to a genomic region in a cell-specific manner. They showed the genome-wide locations of PU.1 binding patterns in macrophages, B-cells, and diffuse B-cell progenitors ^[14]. Similarly, Xu et al. (2012) analyzed chromatin state maps, transcription factor occupancy rates, and gene expression profiles during the development of human erythroid cells at the fetal and adult stages, and carried out a comparative analysis to determine the specific procedures of the development stage ^[15]. Here, it is also important to discuss the study of Choukrallah et al. (2015), who found that the enhancer landscape is dynamically reshaped in each differentiation step. Interesting changes include creating new enhancers and the closing and re-opening of the pre-existing enhancer landscape ^[16]. The authors also reported that the regulatory signatures of two related types of myeloid leukemia expression fusion proteins (RUNX1-ETO and RUNX1-EV1) display a distinct binding pattern and interact with different transcription factors to impact the epigenome ^[17]. A study has also reported that MLL-Af9 and MLL-AF4 oncofusion proteins showed distinct binding patterns in the enhancer region and targeted the RUNX1 program in 11q23 acute myeloid leukemia ^[18]. Enhancers are essential for normal functioning, and the loss of enhancer elements can cause abnormalities; for example, Groschel et al. (2014) showed that the removal of the distal enhancer essential for the GATA2 gene resulted in insufficient Functional GATA2 haploids, which only reduced the expression of the remaining normal alleles ^[19]. This review focuses on a concise and brief overview of the roles of enhancers in development and disease. We attempt to discuss how enhancers are activated and coordinated with transcription factors, as well as the roles of enhancers in mammalian development. This may comprise the first attempt to compile recently published research on development and disease, focusing on enhancers.

2. Features and Types of Enhancers

Enhancers have been identified in the form of various regulatory domains, primed enhancers, active enhancers, and poised enhancers. Each type of enhancer signature has specific histone modification patterns and can be easily identified by these signatures ^[13]^[20]^[21]. Primed enhancers can be identified by only histone H3K4 mono-methylation, while active enhancers signatures are identified by H3K4 mono-methylation and H3K27ac. Finally, the signatures of poised enhancers are marked with H3K4Me1 with H3K27me3, but not H3K27ac ^[13]^[20]^[21]. Active enhancers are linked to expressed genes, while poised enhancers are always associated to developmental genes, which are inactive in embryonic stem cells or precursor cells and become expressed during different differentiation stages ^[22]. During differentiation, the poised enhancer’s signature successfully loses the repressive H3K27me3 histone mark, acquires H3K27ac marks, and becomes active. Enhancers are, thus, subject to dynamic change functions, as an on/off switch to tune the target gene expression and changing the cell state from undifferentiated to differentiated phenotype ^[23]. Hence, the signatures of Poised Enhancers comprise a small set of regulatory signatures in embryonic stem cells that facilitate their timely and stage-specific function, once the correct differentiation signals become available ^[20]. One term also uses super-enhancers (SEs), which are described as large clusters of active enhancers with robust enrichment for binding transcriptional coactivators ^[24]^[25]. These features have also been called stretch enhancers ^[26], multiple enhancers ^[27], and enhancer clusters ^[28], which are similar but not identical between studies (although many of these features overlap). SEs regulate master regulators of pluripotency, such as OCT4, SOX2, and NANOG ^[24]. It has been reported that the SE signature is often enriched near the oncogene in tumor cells, while an enrichment GWAS has identified SNPs normally associated with several common diseases ^[29]^[30].

3. Role of Enhancers in Disease Development

The genome-wide sequencing approach has revealed that enhancers are prime targets for genetic or epigenetic alterations that lead to carcinogenesis ^[5]. The main characteristics of the enhancer signature remain constant for every type of cell (e.g., normal vs. cancer/tumor cells). The difference is that the function of the enhancer signatures differs between normal and cancer cell types; that is, the enhancer’s functional output in tumor/cancer cells differs from that in normal cells ^[31]. Careful examination of enhancer signatures between normal cells and their counterpart in cancer cells has revealed that cancer cells tend to lose enhancers at positions near cell fate-specifying genes and gain enhancer signatures near growth-associated genes ^[32]^[33]^[34]. Furthermore, it has again been confirmed, after comparing normal colon epithelial crypts and colon cancer lines, that thousands of differentially enriched primed enhancer marks (H3K4Me1) were enriched in cancerous cells known as variant enhancer loci (Veli), and these gained mono-methylation sites were not found in normal counterpart cells. In contrast, the lost sites were relatively specific to crypt cells, indicating that the colon cancer cells acquired a more differentiated cell state ^[33]. In the post-GWAS era, there is a lot of conceivable evidence that cancer predisposition genomic variants present in the non-coding genomic region lie within these distal regulatory elements ^[35]^[36]. This finding is based on the overlap between SNPs associated with diseases and genomic signatures, revealing that SNPs associated with risk phenotypes are frequently enriched in expression quantitative traits and open chromatin regions ^[37]^[38]. In cancer cells, risk variants lead to the dysregulation of enhancers, disrupting the fine-tuned target expression of their associated genes and producing a pathological state which leads to abnormal growth. For example, pancreatic-specific differential open regions enriched for non-coding variants (SNPs) have been linked to pancreatic disorders ^[39]. Correspondingly, monocyte-/macrophage-specific enhancer elements enriched with SNPs associated with ulcerative colitis, celiac disease, Crohn’s disease, or systemic lupus erythematosus have been reported ^[40]. Studies are also available in which single base-pair point mutations in the distal enhancer of SCNA and PTF1A have been shown to cause sporadic Parkinson’s disease and pancreatic agenesis ^[41]^[42]. Altered super-enhancer activity has also been reported in many complex human diseases, such as Alzheimer’s, Type 1 diabetes, and autoimmune disorders ^[25]^[28]^[43]^[44]. Furthermore, lost super-enhancers and enhancers acquired somatically have been reported to be associated with numerous cancers ^[25]^[43]. Meanwhile, changes in histone writers, erasers, and altered activity of DNA modifiers such as methyl and acetyltransferases also reshape the chromatin landscape, which finally leads to abnormal growth and development. Based on known enhancer signatures, several studies (Table 1) have explored the alterations in enhancer activity and histone modification patterns which may be correlated with disease development. Evidence for enhancer alterations in cancer, coming from various studies, is summarized in Table 1.

Table 1. Studies investigating the roles of Enhancers in disease development.

Number	Title	Author	Reference
1	Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells	Taub et al., 1982	^[45]
2	A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly	Lettice, L.A. et al., 2003	^[46]
3	Genomic deletion of a long-range bone enhancer misregulates in Van Buchem disease	Loots, G.G. et al., 2005	^[47]
4	A common sex dependent mutations in a RET enhancer underlies Hirschsprung disease risk	Emison, E.S. et al., 2005	^[48]
5	Disruption of an AP2-alpha binding site in an IRF6 enhancer is associated with cleft lip	Rahimov et al., 2008	^[49]
6	Functional enhancers at the gene-poor 8q24 cancer linked locus	Jia, L. et al., 2009	^[50]
7	The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer	Pomeratz, M.M. et al., 2009	^[51]
8	The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced WNT signaling	Tuupanen, S. et al., 2009	^[52]
9	Long-range enhancers on 8q24 regulate c-Myc	Sotelo et al., 2010	^[53]
10	An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer.	Wasserman, N.F. et al., 2010	^[54]
11	Enhancer-adoption as a mechanism of human developmental disease	Lettice, L.A. et al., 2011	^[55]
12	Systematic localization of common disease associated variation in regulatory DNA	Maurano et al., 2012	^[36]
13	Epigenomic enhancer profiling defines a signature of colon cancer	Akhtar-Zaidi, B. et al., 2012	^[33]
14	Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors	Sur et al., 2012	^[56]
15	A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (LMBR1) causes preaxial polydactyly with triphalangeal thumb	Laurell, T. et al., 2012	^[57]
16	Regulatory variation in a TBX5 enhancer leads to isolated congenital heart diseases	Smemo, S. et al., 2012	^[58]
17	DNA methylation of transcriptional enhancers and cancer predisposition	Aran and Hallman et al., 2013	^[59]
18	Discovery and characterization of super-enhancer associated dependencies in diffuse large B cell lymphoma	Chapuy, B. et al., 2013	^[60]
19	Chromatin stretch enhancer states drive cell specific gene regulation and harbor human disease risk variants	Parker, S.C. et al., 2013	^[26]
20	Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation	Shi, J. et al., 2013	^[61]
21	Selective inhibition of tumor oncogenes by disruption of super-enhancers	Loven, J. et al., 2013	^[29]
22	An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level	Bauer, D.E. et al., 2013	^[62]
23	Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia	Bhatia, S. et al., 2013	^[63]
24	Genome-wide analysis of noncoding regulatory mutations in cancer	Weinhold, N. et al., 2014	^[64]
25	A NOTCH driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia	Herranz, D. et al., 2014	^[65]
26	Combinatorial effects of multiple enhancer variants linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits	Corradin, O. et al., 2014	^[27]
27	Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma	Northcott, P.A. et al., 2014	^[66]
28	Microduplications encompassing the sonic hedgehog limb enhancer ZRS are associated with Hass-type polysyndactyly and Laurin Sandrow syndrome	Lohan, S. et al., 2014	^[67]
29	Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility	Seumois, G. et al., 2014	^[68]
30	Oncogenic regulation. An oncogenic Super enhancer formed through somatic mutation of a noncoding intergenic element.	Mansour, M.R. et al., 2014	^[69]
31	A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential	Zhou, H.Y. et al., 2014	^[70]
32	Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype	Fortini, B.L. et al., 2014	^[71]
33	A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3) (q21;q26) by activating EVI1 expression	Yamazaki et al., 2014	^[72]
34	Long range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia	Yashiro-Ohtani et al., 2014	^[73]
35	Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis	Weedon et al., 2014	^[42]
36	A single oncogenic enhancer rearrangement causes concomitant EV1 and GATA2 deregulation in leukemia	Groschel et al., 2014	^[19]
37	Genetic predisposition to neuroblastoma mediated by a LMO1 super enhancer polymorphisms	Oldridge, D.A. et al., 2015	^[74]
38	7q21.3 Deletion involving enhancer sequences within the gene DYNC1I1 presents with intellectual disability and split hand-split foot malformation with decreased penetrance	Delgado, S. and Velinov, M., 2015	^[75]
39	A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)	Giorgio, E. et al., 2015	^[76]
40	Multiple functional variants in long-range enhancer contribute to the risk of SNP rs965513 in thyroid cancer	He, H. et al., 2015	^[77]
41	Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis	Rasmussen et al., 2015	^[78]
42	The Transcriptional cofactor TRIM33 prevents apoptosis B lymphoblastic leukemia by deactivating a single enhancer	Wang et al., 2015	^[79]
43	Super-enhancers delineate disease-associated regulatory nodes in T cells	Vahedi et al., 2015	^[44]
44	Identification of focally amplified lineage-specific super-enhancers in human epithelial cancer	Zhang, X. et al., 2016	^[80]
45	Role of non-coding sequence variants in cancer	Khurana, E. et al., 2016	^[81]
46	Ever-changing landscapes: transcriptional enhancers in development and evolution	Long, H.K. et al., 2016	^[82]
47	Genetic Predisposition to Chronic Lymphocytic Leukemia is mediated by a BMF Super-Enhancer Polymorphisms	Kandaswamy et al., 2016	^[83]
48	DNMT3A Loss drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias	Yang et al., 2016	^[84]
49	Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity	Ooi et al., 2016	^[43]
50	Parkinson associated risk variants in distal enhancers of a-syncuclein modulates target gene expression	Soldner et al., 2016	^[41]
51	Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome	Cohen, A.J. et al., 2017	^[30]
52	Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)	Will, A.J. et al., 2017	^[85]
53	Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, including an RARaalpha Dependency Targetable by SY-1425, a Potent and Selective RARalpha Agonist	MCKeown, M.R. et al., 2017	^[86]
54	Enhancer profiling identifies critical cancer genes and characterize cell identity in adult T-cell leukemia	Wong et al., 2017	^[87]
55	APOBEC signature mutation generate an oncogenic enhancer that drives LMO1 expression in T-ALL Leukemia	Li et al., 2017	^[88]

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Shailendra Maurya

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1. Introduction

2. Features and Types of Enhancers

3. Role of Enhancers in Disease Development

References