Enhancer redundancy in development and disease.
Journal
Nature reviews. Genetics
ISSN: 1471-0064
Titre abrégé: Nat Rev Genet
Pays: England
ID NLM: 100962779
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
accepted:
24
11
2020
pubmed:
15
1
2021
medline:
27
7
2021
entrez:
14
1
2021
Statut:
ppublish
Résumé
Shadow enhancers are seemingly redundant transcriptional cis-regulatory elements that regulate the same gene and drive overlapping expression patterns. Recent studies have shown that shadow enhancers are remarkably abundant and control most developmental gene expression in both invertebrates and vertebrates, including mammals. Shadow enhancers might provide an important mechanism for buffering gene expression against mutations in non-coding regulatory regions of genes implicated in human disease. Technological advances in genome editing and live imaging have shed light on how shadow enhancers establish precise gene expression patterns and confer phenotypic robustness. Shadow enhancers can interact in complex ways and may also help to drive the formation of transcriptional hubs within the nucleus. Despite their apparent redundancy, the prevalence and evolutionary conservation of shadow enhancers underscore their key role in emerging metazoan gene regulatory networks.
Identifiants
pubmed: 33442000
doi: 10.1038/s41576-020-00311-x
pii: 10.1038/s41576-020-00311-x
pmc: PMC8068586
mid: NIHMS1669402
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
324-336Subventions
Organisme : NHGRI NIH HHS
ID : R00 HG009682
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD095246
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
Shlyueva, D., Stampfel, G. & Stark, A. Transcriptional enhancers: from properties to genome-wide predictions. Nat. Rev. Genet. 15, 272–286 (2014).
pubmed: 24614317
Furlong, E. E. M. & Levine, M. Developmental enhancers and chromosome topology. Science 361, 1341–1345 (2018).
pubmed: 30262496
pmcid: 6986801
Long, H. K., Prescott, S. L. & Wysocka, J. Ever-changing landscapes: transcriptional enhancers in development and evolution. Cell 167, 1170–1187 (2016).
pubmed: 27863239
pmcid: 5123704
Schoenfelder, S. & Fraser, P. Long-range enhancer-promoter contacts in gene expression control. Nat. Rev. Genet. 20, 437–455 (2019).
pubmed: 31086298
Andersson, R. & Sandelin, A. Determinants of enhancer and promoter activities of regulatory elements. Nat. Rev. Genet. 21, 71–87 (2020).
pubmed: 31605096
Field, A. & Adelman, K. Evaluating enhancer function and transcription. Annu. Rev. Biochem. 89, 213–234 (2020).
pubmed: 32197056
Visel, A., Rubin, E. M. & Pennacchio, L. A. Genomic views of distant-acting enhancers. Nature 461, 199–205 (2009).
pubmed: 19741700
pmcid: 2923221
Hoch, M., Schröder, C., Seifert, E. & Jäckle, H. cis-acting control elements for Krüppel expression in the Drosophila embryo. EMBO J. 9, 2587–2595 (1990).
pubmed: 2114978
pmcid: 552291
Kassis, J. A. Spatial and temporal control elements of the Drosophila engrailed gene. Genes Dev. 4, 433–443 (1990).
pubmed: 2110923
Zeitlinger, J. et al. Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo. Genes Dev. 21, 385–390 (2007).
pubmed: 17322397
pmcid: 1804326
Jeong, Y., El-Jaick, K., Roessler, E., Muenke, M. & Epstein, D. J. A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers. Development 133, 761–772 (2006).
pubmed: 16407397
Kurokawa, D. et al. Regulation of Otx2 expression and its functions in mouse forebrain and midbrain. Development 131, 3319–3331 (2004).
pubmed: 15201224
Hong, J.-W., Hendrix, D. A. & Levine, M. S. Shadow enhancers as a source of evolutionary novelty. Science 321, 1314 (2008). This article introduces the term ‘shadow enhancer’ to describe several enhancers important for dorsal–ventral patterning in the fly embryo and speculates on the evolutionary role of shadow enhancers.
pubmed: 18772429
pmcid: 4257485
Barolo, S. Shadow enhancers: frequently asked questions about distributed cis-regulatory information and enhancer redundancy. Bioessays 34, 135–141 (2012).
pubmed: 22083793
Hobert, O. Gene regulation: enhancers stepping out of the shadow. Curr. Biol. 20, R697–R699 (2010).
pubmed: 20833307
Cannavò, E. et al. Shadow enhancers are pervasive features of developmental regulatory networks. Curr. Biol. 26, 38–51 (2016). In this study, the authors identify more than 1,000 shadow enhancers that pattern D. melanogaster mesoderm; sequence conservation suggests that these shadow enhancers play a key role in development.
pubmed: 26687625
pmcid: 4712172
Wunderlich, Z. et al. Krüppel expression levels are maintained through compensatory evolution of shadow enhancers. Cell Rep. 12, 1740–1747 (2015).
pubmed: 26344774
pmcid: 4581983
Antosova, B. et al. The gene regulatory network of lens induction is wired through meis-dependent shadow enhancers of Pax6. PLoS Genet. 12, e1006441 (2016). This is one of the first studies to examine the phenotypic impact of double shadow enhancer deletions and shadow enhancer deletions on a sensitized background in mice.
pubmed: 27918583
pmcid: 5137874
Letelier, J. et al. A conserved Shh cis-regulatory module highlights a common developmental origin of unpaired and paired fins. Nat. Genet. 50, 504–509 (2018).
pubmed: 29556077
pmcid: 5896732
Nolte, C., Jinks, T., Wang, X., Martinez Pastor, M. T. & Krumlauf, R. Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development. Dev. Biol. 383, 158–173 (2013).
pubmed: 24055171
Swami, M. Transcription: shadow enhancers confer robustness. Nat. Rev. Genet. 11, 454 (2010).
pubmed: 20548292
Ghiasvand, N. M. et al. Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease. Nat. Neurosci. 14, 578–586 (2011).
pubmed: 21441919
pmcid: 3083485
Watts, J. A. et al. Study of FoxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development. PLoS Genet. 7, e1002277 (2011).
pubmed: 21935353
pmcid: 3174211
Lagha, M., Bothma, J. P. & Levine, M. Mechanisms of transcriptional precision in animal development. Trends Genet. 28, 409–416 (2012).
pubmed: 22513408
pmcid: 4257495
Stefanakis, N., Carrera, I. & Hobert, O. Regulatory logic of pan-neuronal gene expression in C. elegans. Neuron 87, 733–750 (2015).
pubmed: 26291158
pmcid: 4545498
Frankel, N. et al. Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466, 490–493 (2010). This article describes the phenotypic impact of shadow enhancer deletions on bristle formation in fly larvae. Along with Perry et al. (2010), it was among the first to show that shadow enhancers are required for proper development under stressful conditions.
pubmed: 20512118
pmcid: 2909378
Perry, M. W., Boettiger, A. N., Bothma, J. P. & Levine, M. Shadow enhancers foster robustness of Drosophila gastrulation. Curr. Biol. 20, 1562–1567 (2010). This article describes the phenotypic impact of shadow enhancer deletions on gastrulation in fly embryos. Along with Frankel et al. (2010), it was among the first to show that shadow enhancers are required for proper development under stressful conditions.
pubmed: 20797865
pmcid: 4257487
Perry, M. W., Boettiger, A. N. & Levine, M. Multiple enhancers ensure precision of gap gene-expression patterns in the Drosophila embryo. Proc. Natl Acad. Sci. USA 108, 13570–13575 (2011).
pubmed: 21825127
pmcid: 3158186
Osterwalder, M. et al. Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554, 239–243 (2018). This study uses mouse ENCODE data and systematic deletions (both individual and pairs) of ten different mouse limb enhancers to show widespread redundancy in mammalian genomes.
pubmed: 29420474
pmcid: 5808607
Sagai, T. et al. SHH signaling directed by two oral epithelium-specific enhancers controls tooth and oral development. Sci. Rep. 7, 13004 (2017).
pubmed: 29021530
pmcid: 5636896
Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).
pubmed: 24670763
pmcid: 5215096
Yue, F. et al. A comparative encyclopedia of DNA elements in the mouse genome. Nature 515, 355–364 (2014).
pubmed: 25409824
pmcid: 4266106
Roadmap Epigenomics Consortium. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).
pmcid: 4530010
Abascal, F. et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583, 699–710 (2020).
Gorkin, D. U. et al. An atlas of dynamic chromatin landscapes in mouse fetal development. Nature 583, 744–751 (2020).
pubmed: 32728240
pmcid: 7398618
Dekker, J. et al. The 4D nucleome project. Nature 549, 219–226 (2017).
pubmed: 28905911
pmcid: 5617335
Visel, A., Minovitsky, S., Dubchak, I. & Pennacchio, L. A. VISTA Enhancer Browser—a database of tissue-specific human enhancers. Nucleic Acids Res. 35, D88–D92 (2007).
pubmed: 17130149
Pennacchio, L. A. et al. In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499–502 (2006).
pubmed: 17086198
Manning, L. et al. A resource for manipulating gene expression and analyzing cis-regulatory modules in the Drosophila CNS. Cell Rep. 2, 1002–1013 (2012).
pubmed: 23063363
pmcid: 3523218
Kvon, E. Z. Using transgenic reporter assays to functionally characterize enhancers in animals. Genomics 106, 185–192 (2015).
pubmed: 26072435
Gallo, S. M. et al. REDfly v3.0: toward a comprehensive database of transcriptional regulatory elements in Drosophila. Nucleic Acids Res. 39, D118–D123 (2011).
pubmed: 20965965
Bonn, S. et al. Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. Nat. Genet. 44, 148–156 (2012).
pubmed: 22231485
Kvon, E. Z. et al. Genome-scale functional characterization of Drosophila developmental enhancers in vivo. Nature 512, 91–95 (2014).
pubmed: 24896182
Lopes, R., Korkmaz, G. & Agami, R. Applying CRISPR-Cas9 tools to identify and characterize transcriptional enhancers. Nat. Rev. Mol. Cell Biol. 17, 597–604 (2016).
pubmed: 27381243
Catarino, R. R. & Stark, A. Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation. Genes Dev. 32, 202–223 (2018).
pubmed: 29491135
pmcid: 5859963
Klein, J. C., Chen, W., Gasperini, M. & Shendure, J. Identifying novel enhancer elements with CRISPR-based screens. ACS Chem. Biol. 13, 326–332 (2018).
pubmed: 29300083
pmcid: 6218247
Wright, J. B. & Sanjana, N. E. CRISPR screens to discover functional noncoding elements. Trends Genet. 32, 526–529 (2016).
pubmed: 27423542
pmcid: 4992445
Garcia, H. G., Tikhonov, M., Lin, A. & Gregor, T. Quantitative imaging of transcription in living Drosophila embryos links polymerase activity to patterning. Curr. Biol. 23, 2140–2145 (2013).
pubmed: 24139738
Lucas, T. et al. Live imaging of bicoid-dependent transcription in Drosophila embryos. Curr. Biol. 23, 2135–2139 (2013).
pubmed: 24139736
Twell, D., Yamaguchi, J., Wing, R. A., Ushiba, J. & McCormick, S. Promoter analysis of genes that are coordinately expressed during pollen development reveals pollen-specific enhancer sequences and shared regulatory elements. Genes Dev. 5, 496–507 (1991).
pubmed: 1840556
Poulsen, C. & Chua, N. H. Dissection of 5’ upstream sequences for selective expression of the Nicotiana plumbaginifolia rbcS-8B gene. Mol. Gen. Genet. 214, 16–23 (1988).
pubmed: 3226423
Camprodón, F. J. & Castelli-Gair, J. E. Ultrabithorax protein expression in breakpoint mutants: localization of single, co-operative and redundant cis regulatory elements. Rouxs. Arch. Dev. Biol. 203, 411–421 (1994).
pubmed: 28305947
Bachmann, A. & Knust, E. Dissection of cis-regulatory elements of the Drosophila gene Serrate. Dev. Genes Evol. 208, 346–351 (1998).
pubmed: 9716725
Schroeder, M. D. et al. Transcriptional control in the segmentation gene network of Drosophila. PLoS Biol. 2, E271 (2004).
pubmed: 15340490
pmcid: 514885
Pappu, K. S. et al. Dual regulation and redundant function of two eye-specific enhancers of the Drosophila retinal determination gene dachshund. Development 132, 2895–2905 (2005).
pubmed: 15930118
Yao, L. C. et al. Multiple modular promoter elements drive graded brinker expression in response to the Dpp morphogen gradient. Development 135, 2183–2192 (2008).
pubmed: 18506030
Ertzer, R. et al. Cooperation of sonic hedgehog enhancers in midline expression. Dev. Biol. 301, 578–589 (2007).
pubmed: 17157288
Nakada, Y., Parab, P., Simmons, A., Omer-Abdalla, A. & Johnson, J. E. Separable enhancer sequences regulate the expression of the neural bHLH transcription factor neurogenin 1. Dev. Biol. 271, 479–487 (2004).
pubmed: 15223348
Menke, D. B., Guenther, C. & Kingsley, D. M. Dual hindlimb control elements in the Tbx4 gene and region-specific control of bone size in vertebrate limbs. Development 135, 2543–2553 (2008).
pubmed: 18579682
Li, Q., Peterson, K. R., Fang, X. & Stamatoyannopoulos, G. Locus control regions. Blood 100, 3077–3086 (2002).
pubmed: 12384402
Grosveld, F., van Assendelft, G. B., Greaves, D. R. & Kollias, G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell 51, 975–985 (1987).
pubmed: 3690667
Zhou, X. & Sigmund, C. D. Chorionic enhancer is dispensable for regulated expression of the human renin gene. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R279 (2008).
pubmed: 18077515
Allan, C. M., Walker, D. & Taylor, J. M. Evolutionary duplication of a hepatic control region in the human apolipoprotein E gene locus. Identification of a second region that confers high level and liver-specific expression of the human apolipoprotein E gene in transgenic mice. J. Biol. Chem. 270, 26278–26281 (1995).
pubmed: 7592836
Babbitt, C. C., Markstein, M. & Gray, J. M. Recent advances in functional assays of transcriptional enhancers. Genomics 106, 137–139 (2015).
pubmed: 26100358
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
pubmed: 24119843
Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).
pubmed: 23582322
pmcid: 3653129
Parker, S. C. J. et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl Acad. Sci. USA 110, 17921–17926 (2013).
pubmed: 24127591
pmcid: 3816444
Hay, D. et al. Genetic dissection of the α-globin super-enhancer in vivo. Nat. Genet. 48, 895–903 (2016).
pubmed: 27376235
pmcid: 5058437
Pott, S. & Lieb, J. D. What are super-enhancers? Nat. Genet. 47, 8–12 (2015).
pubmed: 25547603
Dukler, N., Gulko, B., Huang, Y.-F. & Siepel, A. Is a super-enhancer greater than the sum of its parts? Nat. Genet. 49, 2–3 (2016).
pubmed: 28029159
pmcid: 5379849
Li, W., Notani, D. & Rosenfeld, M. G. Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat. Rev. Genet. 17, 207–223 (2016).
pubmed: 26948815
Arner, E. et al. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347, 1010–1014 (2015).
pubmed: 25678556
pmcid: 4681433
Wang, X. & Goldstein, D. B. Enhancer domains predict gene pathogenicity and inform gene discovery in complex disease. Am. J. Hum. Genet. 106, 215–233 (2020). This study uses human chromatin data from the Roadmap Epigenomics Consortium to show that human genes with large redundant domains are depleted of cis-acting genetic variants that disrupt gene expression, and their expression is buffered against the effects of disruptive non-coding mutations.
pubmed: 32032514
pmcid: 7010980
Arnold, C. D. et al. Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339, 1074–1077 (2013).
pubmed: 23328393
Wang, H. et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153, 910–918 (2013).
pubmed: 23643243
pmcid: 3969854
Joung, J. K. & Sander, J. D. TALENs: a widely applicable technology for targeted genome editing. Nat. Rev. Mol. Cell Biol. 14, 49–55 (2013).
pubmed: 23169466
Doudna, J. A. & Charpentier, E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 346, 1258096 (2014).
pubmed: 25430774
Dickel, D. E. et al. Ultraconserved enhancers are required for normal development. Cell 172, 491–499.e15 (2018).
pubmed: 29358049
pmcid: 5786478
Waymack, R., Fletcher, A., Enciso, G. & Wunderlich, Z. Shadow enhancers can suppress input transcription factor noise through distinct regulatory logic. eLife 9, e59351 (2020). This study in fly embryos shows that a pair of shadow enhancers, each regulated by different TFs, drives lower expression noise than do single or duplicated enhancers.
pubmed: 32804082
pmcid: 7556877
Visel, A. et al. Functional autonomy of distant-acting human enhancers. Genomics 93, 509–513 (2009).
pubmed: 19268701
Bothma, J. P. et al. Enhancer additivity and non-additivity are determined by enhancer strength in the Drosophila embryo. eLife 4, e07956 (2015). This article investigates how the activities of individual shadow enhancers interact to establish their combined activity in fly embryos and finds a wide range of possible interactions (superadditive, additive, subadditive and repressive) that may depend on the strength of the individual enhancers.
pmcid: 4532966
Lam, D. D. et al. Partially redundant enhancers cooperatively maintain mammalian Pomc expression above a critical functional threshold. PLoS Genet. 11, e1004935 (2015).
pubmed: 25671638
pmcid: 4335486
Scholes, C., Biette, K. M., Harden, T. T. & DePace, A. H. Signal integration by shadow enhancers and enhancer duplications varies across the Drosophila embryo. Cell Rep. 26, 2407–2418.e5 (2019).
pubmed: 30811990
pmcid: 6597254
El-Sherif, E. & Levine, M. Shadow enhancers mediate dynamic shifts of gap gene expression in the drosophila embryo. Curr. Biol. 26, 1164–1169 (2016).
pubmed: 27112292
pmcid: 4957242
Dunipace, L., Ozdemir, A. & Stathopoulos, A. Complex interactions between cis-regulatory modules in native conformation are critical for Drosophila snail expression. Development 138, 4075–4084 (2011).
pubmed: 21813571
pmcid: 3160101
Dunipace, L., Ákos, Z. & Stathopoulos, A. Coacting enhancers can have complementary functions within gene regulatory networks and promote canalization. PLoS Genet. 15, e1008525 (2019).
pubmed: 31830033
pmcid: 6932828
Yan, J. et al. Regulatory logic driving stable levels of defective proventriculus expression during terminal photoreceptor specification in flies. Development 144, 844–855 (2017).
pubmed: 28126841
pmcid: 5374349
Bentovim, L., Harden, T. T. & DePace, A. H. Transcriptional precision and accuracy in development: from measurements to models and mechanisms. Development 144, 3855–3866 (2017).
pubmed: 29089359
pmcid: 5702068
Robson, M. I., Ringel, A. R. & Mundlos, S. Regulatory landscaping: how enhancer-promoter communication is sculpted in 3D. Mol. Cell 74, 1110–1122 (2019).
pubmed: 31226276
Zabidi, M. A. & Stark, A. Regulatory enhancer-core-promoter communication via transcription factors and cofactors. Trends Genet. 32, 801–814 (2016).
pubmed: 27816209
pmcid: 6795546
Proudhon, C. et al. Active and inactive enhancers cooperate to exert localized and long-range control of gene regulation. Cell Rep. 15, 2159–2169 (2016).
pubmed: 27239026
pmcid: 4899175
Jiang, T. et al. Identification of multi-loci hubs from 4C-seq demonstrates the functional importance of simultaneous interactions. Nucleic Acids Res. 44, 8714–8725 (2016).
pubmed: 27439714
pmcid: 5062970
Hughes, J. R. et al. Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nat. Genet. 46, 205–212 (2014).
pubmed: 24413732
Allahyar, A. et al. Enhancer hubs and loop collisions identified from single-allele topologies. Nat. Genet. 50, 1151–1160 (2018).
pubmed: 29988121
Fukaya, T., Lim, B. & Levine, M. Enhancer control of transcriptional bursting. Cell 166, 358–368 (2016).
pubmed: 27293191
pmcid: 4970759
Lim, B., Heist, T., Levine, M. & Fukaya, T. Visualization of transvection in living drosophila embryos. Mol. Cell 70, 287–296.e6 (2018).
pubmed: 29606591
pmcid: 6092965
Godin, A. G., Lounis, B. & Cognet, L. Super-resolution microscopy approaches for live cell imaging. Biophys. J. 107, 1777–1784 (2014).
pubmed: 25418158
pmcid: 4213717
Schermelleh, L. et al. Super-resolution microscopy demystified. Nat. Cell Biol. 21, 72–84 (2019).
pubmed: 30602772
Chen, H. et al. Dynamic interplay between enhancer-promoter topology and gene activity. Nat. Genet. 50, 1296–1303 (2018).
pubmed: 30038397
pmcid: 6119122
Chen, H. & Gregor, T. in RNA Tagging: Methods and Protocols (ed. Heinlein, M.) 373–384 (Springer, 2020).
Reiter, F., Wienerroither, S. & Stark, A. Combinatorial function of transcription factors and cofactors. Curr. Opin. Genet. Dev. 43, 73–81 (2017).
pubmed: 28110180
Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).
pubmed: 29930091
pmcid: 6092193
Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K. & Sharp, P. A. A phase separation model for transcriptional control. Cell 169, 13–23 (2017).
pubmed: 28340338
pmcid: 5432200
Montavon, T. et al. A regulatory archipelago controls Hox genes transcription in digits. Cell 147, 1132–1145 (2011).
pubmed: 22118467
Cho, W.-K. et al. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates. Science 361, 412–415 (2018).
pubmed: 29930094
pmcid: 6543815
Jackson, D. A., Iborra, F. J., Manders, E. M. & Cook, P. R. Numbers and organization of RNA polymerases, nascent transcripts, and transcription units in HeLa nuclei. Mol. Biol. Cell 9, 1523–1536 (1998).
pubmed: 9614191
pmcid: 25378
Cisse, I. I. et al. Real-time dynamics of RNA polymerase II clustering in live human cells. Science 341, 664–667 (2013).
pubmed: 23828889
Benabdallah, N. S. et al. Decreased enhancer-promoter proximity accompanying enhancer activation. Mol. Cell 76, 473–484.e7 (2019).
pubmed: 31494034
pmcid: 6838673
Alexander, J. M. et al. Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity. eLife 8, e41769 (2019).
pubmed: 31124784
pmcid: 6534382
Tsai, A., Alves, M. R. & Crocker, J. Multi-enhancer transcriptional hubs confer phenotypic robustness. eLife 8, e45325 (2019). This study describes how shadow enhancers may be critical for establishing or maintaining local regions of high TF concentrations required for achieving a certain threshold of gene expression.
pubmed: 31294690
pmcid: 6650246
Zeitlinger, J. & Stark, A. Developmental gene regulation in the era of genomics. Dev. Biol. 339, 230–239 (2010).
pubmed: 20045679
Cretekos, C. J. et al. Regulatory divergence modifies limb length between mammals. Genes Dev. 22, 141–151 (2008).
pubmed: 18198333
pmcid: 2192750
Manis, J. P. et al. Class switching in B cells lacking 3′ immunoglobulin heavy chain enhancers. J. Exp. Med. 188, 1421–1431 (1998).
pubmed: 9782119
pmcid: 2213411
Bender, M. A. et al. Description and targeted deletion of 5’ hypersensitive site 5 and 6 of the mouse beta-globin locus control region. Blood 92, 4394–4403 (1998).
pubmed: 9834246
Fiering, S. et al. Targeted deletion of 5’HS2 of the murine beta-globin LCR reveals that it is not essential for proper regulation of the beta-globin locus. Genes Dev. 9, 2203–2213 (1995).
pubmed: 7557375
Attanasio, C. et al. Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342, 1241006 (2013).
pubmed: 24159046
pmcid: 3991470
Nolte, M. J. et al. Functional analysis of limb transcriptional enhancers in the mouse. Evol. Dev. 16, 207–223 (2014).
pubmed: 24920384
pmcid: 4130292
Ahituv, N. et al. Deletion of ultraconserved elements yields viable mice. PLoS Biol. 5, e234 (2007).
pubmed: 17803355
pmcid: 1964772
Cunningham, T. J., Lancman, J. J., Berenguer, M., Dong, P. D. S. & Duester, G. Genomic knockout of two presumed forelimb Tbx5 enhancers reveals they are nonessential for limb development. Cell Rep. 23, 3146–3151 (2018).
pubmed: 29898387
pmcid: 6034701
Hill, R. E. & Lettice, L. A. Alterations to the remote control of Shh gene expression cause congenital abnormalities. Phil. Trans. R. Soc. B 368, 20120357 (2013).
pubmed: 23650631
pmcid: 3682722
Gupta, R. M. et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170, 522–533.e15 (2017).
pubmed: 28753427
pmcid: 5785707
Huang, L. et al. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am. J. Hum. Genet. 91, 694–702 (2012).
pubmed: 23000143
pmcid: 3484651
Wright, J. B., Brown, S. J. & Cole, M. D. Upregulation of c-MYC in cis through a large chromatin loop linked to a cancer risk-associated single-nucleotide polymorphism in colorectal cancer cells. Mol. Cell. Biol. 30, 1411–1420 (2010).
pubmed: 20065031
pmcid: 2832500
Sur, I. K. et al. Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science 338, 1360–1363 (2012).
pubmed: 23118011
Oktay, Y. et al. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation. Sci. Rep. 6, 27569 (2016).
pubmed: 27282637
pmcid: 4901315
Inoue, F. & Ahituv, N. Decoding enhancers using massively parallel reporter assays. Genomics 106, 159–164 (2015).
pubmed: 26072433
Kvon, E. Z. et al. Comprehensive in vivo interrogation reveals phenotypic impact of human enhancer variants. Cell 180, 1262–1271.e15 (2020).
pubmed: 32169219
pmcid: 7179509
Kircher, M. et al. Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. Nat. Commun. 10, 3583 (2019).
pubmed: 31395865
pmcid: 6687891
Canver, M. C. et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527, 192–197 (2015).
pubmed: 26375006
pmcid: 4644101
Saleque, S. et al. Dyad symmetry within the mouse 3’ IgH regulatory region includes two virtually identical enhancers (C alpha3’E and hs3). J. Immunol. 158, 4780–4787 (1997).
pubmed: 9144492
Barth, N. K. H., Li, L. & Taher, L. Independent transposon exaptation is a widespread mechanism of redundant enhancer evolution in the mammalian genome. Genome Biol. Evol. 12, 1–17 (2020).
pubmed: 31950992
pmcid: 7093719
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016).
pubmed: 26941318
pmcid: 4887275
Franchini, L. F. et al. Convergent evolution of two mammalian neuronal enhancers by sequential exaptation of unrelated retroposons. Proc. Natl Acad. Sci. USA 108, 15270–15275 (2011).
pubmed: 21876128
pmcid: 3174587
Ludwig, M. Z., Bergman, C., Patel, N. H. & Kreitman, M. Evidence for stabilizing selection in a eukaryotic enhancer element. Nature 403, 564–567 (2000).
pubmed: 10676967
Arnold, C. D. et al. Quantitative genome-wide enhancer activity maps for five Drosophila species show functional enhancer conservation and turnover during cis-regulatory evolution. Nat. Genet. 46, 685–692 (2014).
pubmed: 24908250
pmcid: 4250274
Berthelot, C., Villar, D., Horvath, J. E., Odom, D. T. & Flicek, P. Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression. Nat. Ecol. Evol. 2, 152–163 (2018).
pubmed: 29180706
Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).
pubmed: 22955828
pmcid: 3771521
McGuire, A. L. et al. The road ahead in genetics and genomics. Nat. Rev. Genet. 21, 581–596 (2020).
pubmed: 32839576
pmcid: 7444682
Short, P. J. et al. De novo mutations in regulatory elements in neurodevelopmental disorders. Nature 555, 611–616 (2018).
pubmed: 29562236
pmcid: 5912909
Turro, E. et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature 583, 96–102 (2020).
pubmed: 32581362
pmcid: 7610553
Richter, F. et al. Genomic analyses implicate noncoding de novo variants in congenital heart disease. Nat. Genet. 52, 769–777 (2020).
pubmed: 32601476
pmcid: 7415662
Turner, T. N. et al. Genomic patterns of De novo mutation in simplex autism. Cell 171, 710–722.e12 (2017).
pubmed: 28965761
pmcid: 5679715
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).
pubmed: 32461654
pmcid: 7334197
1000 Genomes Project Consortium. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed program. Preprint at bioRxiv https://doi.org/10.1101/563866 (2019).
doi: 10.1101/563866
van Arensbergen, J. et al. High-throughput identification of human SNPs affecting regulatory element activity. Nat. Genet. 51, 1160–1169 (2019).
pubmed: 31253979
pmcid: 6609452
O’Meara, M. M. et al. Cis-regulatory mutations in the Caenorhabditis elegans homeobox gene locus cog-1 affect neuronal development. Genetics 181, 1679–1686 (2009).
pubmed: 19189954
pmcid: 2666530
Fujioka, M. & Jaynes, J. B. Regulation of a duplicated locus: Drosophila sloppy paired is replete with functionally overlapping enhancers. Dev. Biol. 362, 309–319 (2012).
pubmed: 22178246
Bell, K., Skier, K., Chen, K. H. & Gergen, J. P. Two pair-rule responsive enhancers regulate wingless transcription in the Drosophila blastoderm embryo. Dev. Dyn. 249, 556–572 (2020).
pubmed: 31837063
Kalay, G., Lachowiec, J., Rosas, U., Dome, M. R. & Wittkopp, P. Redundant and cryptic enhancer activities of the drosophila yellow gene. Genetics 212, 343–360 (2019).
pubmed: 30842209
pmcid: 6499527
Johnson, W. A., McCormick, C. A., Bray, S. J. & Hirsh, J. A neuron-specific enhancer of the Drosophila dopa decarboxylase gene. Genes Dev. 3, 676–686 (1989).
pubmed: 2501149
Torbey, P. et al. Cooperation, cis-interactions, versatility and evolutionary plasticity of multiple cis-acting elements underlie krox20 hindbrain regulation. PLoS Genet. 14, e1007581 (2018).
pubmed: 30080860
pmcid: 6095606
Yao, Y. et al. Cis-regulatory architecture of a brain signaling center predates the origin of chordates. Nat. Genet. 48, 575–580 (2016).
pubmed: 27064252
pmcid: 4848136
de Souza, F. S. J. et al. Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting. Mol. Cell. Biol. 25, 3076–3086 (2005).
pubmed: 15798195
pmcid: 1069613
Degenhardt, K. R. et al. Distinct enhancers at the Pax3 locus can function redundantly to regulate neural tube and neural crest expressions. Dev. Biol. 339, 519–527 (2010).
pubmed: 20045680
pmcid: 2830354
McGreal-Estrada, R. S., Wolf, L. V. & Cvekl, A. Promoter-enhancer looping and shadow enhancers of the mouse αA-crystallin locus. Biol. Open 7, bio036897 (2018).
pubmed: 30404901
pmcid: 6310886
Berlivet, S. et al. Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs. PLoS Genet. 9, e1004018 (2013).
pubmed: 24385922
pmcid: 3873244
Will, A. J. et al. Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). Nat. Genet. 49, 1539–1545 (2017).
pubmed: 28846100
pmcid: 5617800
Miesfeld, J. B. et al. The Atoh7 remote enhancer provides transcriptional robustness during retinal ganglion cell development. Proc. Natl Acad. Sci. USA 117, 21690–21700 (2020).
pubmed: 32817515
pmcid: 7474671
Dimanlig, P. V., Faber, S. C., Auerbach, W., Makarenkova, H. P. & Lang, R. A. The upstream ectoderm enhancer in Pax6 has an important role in lens induction. Development 128, 4415–4424 (2001).
pubmed: 11714668
Hui, C. C. & Joyner, A. L. A mouse model of Greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat. Genet. 3, 241–246 (1993).
pubmed: 8387379
Hogan, B. L. et al. Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse. J. Embryol. Exp. Morphol. 97, 95–110 (1986).
pubmed: 3794606
Hill, R. E. et al. Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature 354, 522–525 (1991).
pubmed: 1684639