1932

Abstract

The successful development and ongoing functioning of complex organisms depend on the faithful execution of the genetic code. A critical step in this process is the correct spatial and temporal expression of genes. The highly orchestrated transcription of genes is controlled primarily by regulatory elements: promoters, enhancers, and insulators. The medical importance of this key biological process can be seen by the frequency with which mutations and inherited variants that alter regulatory elements lead to monogenic and complex diseases and cancer. Here, we provide an overview of the methods available to characterize and perturb gene regulatory circuits. We then highlight mechanisms through which regulatory rewiring contributes to disease, and conclude with a perspective on how our understanding of gene regulation can be used to improve human health.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-112921-010715
2022-08-31
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/genom/23/1/annurev-genom-112921-010715.html?itemId=/content/journals/10.1146/annurev-genom-112921-010715&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Abel HJ, Larson DE, Regier AA, Chiang C, Das I et al. 2020. Mapping and characterization of structural variation in 17,795 human genomes. Nature 583:83–89
    [Google Scholar]
  2. 2.
    Allen EK, Randolph AG, Bhangale T, Dogra P, Ohlson M et al. 2017. SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. Nat. Med. 23:975–83
    [Google Scholar]
  3. 3.
    Amabile A, Migliara A, Capasso P, Biffi M, Cittaro D et al. 2016. Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell 167:219–32.e14
    [Google Scholar]
  4. 4.
    Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F et al. 2013. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat. Genet. 45:912–17
    [Google Scholar]
  5. 5.
    Anzalone AV, Koblan LW, Liu DR. 2020. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat. Biotechnol. 38:824–44
    [Google Scholar]
  6. 6.
    Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW et al. 2019. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576:149–57Described the development of a versatile genomic editing system that can encode any sequence change.
    [Google Scholar]
  7. 7.
    Apta-Smith MJ, Hernandez-Fernaud JR, Bowman AJ. 2018. Evidence for the nuclear import of histones H3.1 and H4 as monomers. EMBO J 37:e98714
    [Google Scholar]
  8. 8.
    Avsec Ž, Agarwal V, Visentin D, Ledsam JR, Grabska-Barwinska A et al. 2021. Effective gene expression prediction from sequence by integrating long-range interactions. Nat. Methods 18:1196–203
    [Google Scholar]
  9. 9.
    Badat M, Davies JOJ, Fisher C, Downes DJ, Rose A et al. 2021. A remarkable case of HbH disease illustrates the relative contributions of the α-globin enhancers to gene expression. Blood 137:527–75
    [Google Scholar]
  10. 10.
    Banerji J, Rusconi S, Schaffner W. 1981. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27:299–308
    [Google Scholar]
  11. 11.
    Bartosovic M, Kabbe M, Castelo-Branco G. 2021. Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues. Nat. Biotechnol. 39:825–35
    [Google Scholar]
  12. 12.
    Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y et al. 2013. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342:253–57
    [Google Scholar]
  13. 13.
    Beagrie RA, Scialdone A, Schueler M, Kraemer DCA, Chotalia M et al. 2017. Complex multi-enhancer contacts captured by genome architecture mapping. Nature 543:519–24
    [Google Scholar]
  14. 14.
    Bentsen M, Goymann P, Schultheis H, Klee K, Petrova A et al. 2020. ATAC-seq footprinting unravels kinetics of transcription factor binding during zygotic genome activation. Nat. Commun. 11:4267
    [Google Scholar]
  15. 15.
    Beyter D, Ingimundardottir H, Oddsson A, Eggertsson HP, Bjornsson E et al. 2021. Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits. Nat. Genet. 53:779–86
    [Google Scholar]
  16. 16.
    Bhatia S, Bengani H, Fish M, Brown A, Divizia MT et al. 2013. Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. Am. J. Hum. Genet. 93:1126–34
    [Google Scholar]
  17. 17.
    Bikard D, Jiang W, Samai P, Hochschild A, Zhang F, Marraffini LA. 2013. Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Nucleic Acids Res 41:7429–37
    [Google Scholar]
  18. 18.
    Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH et al. 2008. High-resolution mapping and characterization of open chromatin across the genome. Cell 132:311–22
    [Google Scholar]
  19. 19.
    Bozhilov YK, Downes DJ, Telenius J, Oudelaar AM, Olivier EN et al. 2021. A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker. Nat. Commun. 12:3806
    [Google Scholar]
  20. 20.
    Brant L, Georgomanolis T, Nikolic M, Brackley CA, Kolovos P et al. 2016. Exploiting native forces to capture chromosome conformation in mammalian cell nuclei. Mol. Syst. Biol. 12:891
    [Google Scholar]
  21. 21.
    Brosh R, Laurent JM, Ordoñez R, Huang E, Hogan MS et al. 2021. A versatile platform for locus-scale genome rewriting and verification. PNAS 118:e2023952118
    [Google Scholar]
  22. 22.
    Buenrostro JD, Corces MR, Lareau CA, Wu B, Schep AN et al. 2018. Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation. Cell 173:1535–48.e16
    [Google Scholar]
  23. 23.
    Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. 2013. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10:1213–18
    [Google Scholar]
  24. 24.
    Buenrostro JD, Wu B, Litzenburger UM, Ruff D, Gonzales ML et al. 2015. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523:486–90
    [Google Scholar]
  25. 25.
    Calderon D, Nguyen MLT, Mezger A, Kathiria A, Müller F et al. 2019. Landscape of stimulation-responsive chromatin across diverse human immune cells. Nat. Genet. 51:1494–505
    [Google Scholar]
  26. 26.
    Caron B, Luo Y, Rausell A. 2019. NCBoost classifies pathogenic non-coding variants in Mendelian diseases through supervised learning on purifying selection signals in humans. Genome Biol 20:32
    [Google Scholar]
  27. 27.
    Carter B, Ku WL, Kang JY, Hu G, Perrie J et al. 2019. Mapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq). Nat. Commun. 10:3747
    [Google Scholar]
  28. 28.
    Chen X-F, Zhu D-L, Yang M, Hu W-X, Duan Y-Y et al. 2018. An osteoporosis risk SNP at 1p36.12 acts as an allele-specific enhancer to modulate LINC00339 expression via long-range loop formation. Am. J. Hum. Genet. 102:776–93
    [Google Scholar]
  29. 29.
    Claussnitzer M, Dankel SN, Kim K-H, Quon G, Meuleman W et al. 2015. FTO obesity variant circuitry and adipocyte browning in humans. N. Engl. J. Med. 373:895–907
    [Google Scholar]
  30. 30.
    Coelho A, Picanço I, Seuanes F, Seixas MT, Faustino P 2010. Novel large deletions in the human α-globin gene cluster: clarifying the HS-40 long-range regulatory role in the native chromosome environment. Blood Cells Mol. Dis. 45:147–53
    [Google Scholar]
  31. 31.
    Corces MR, Buenrostro JD, Wu B, Greenside PG, Chan SM et al. 2016. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat. Genet. 48:1193–203
    [Google Scholar]
  32. 32.
    Corces MR, Trevino AE, Hamilton EG, Greenside PG, Sinnott-Armstrong NA et al. 2017. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat. Methods 14:959–62
    [Google Scholar]
  33. 33.
    Core LJ, Waterfall JJ, Lis JT. 2008. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322:1845–48
    [Google Scholar]
  34. 34.
    Cusanovich DA, Daza R, Adey A, Pliner HA, Christiansen L et al. 2015. Multiplex single-cell profiling of chromatin accessibility by combinatorial cellular indexing. Science 348:910–14
    [Google Scholar]
  35. 35.
    Dainese R, Gardeux V, Llimos G, Alpern D, Jiang JY et al. 2020. A parallelized, automated platform enabling individual or sequential ChIP of histone marks and transcription factors. PNAS 117:13828–38
    [Google Scholar]
  36. 36.
    Dao LTM, Galindo-Albarrán AO, Castro-Mondragon JA, Andrieu-Soler C, Medina-Rivera A et al. 2017. Genome-wide characterization of mammalian promoters with distal enhancer functions. Nat. Genet. 49:1073–81
    [Google Scholar]
  37. 37.
    Davidson AE, Liskova P, Evans CJ, Dudakova L, Nosková L et al. 2016. Autosomal-dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2. Am. J. Hum. Genet. 98:75–89
    [Google Scholar]
  38. 38.
    Davies JOJ, Oudelaar AM, Higgs DR, Hughes JR. 2017. How best to identify chromosomal interactions: a comparison of approaches. Nat. Methods 14:125–34
    [Google Scholar]
  39. 39.
    Davies JOJ, Telenius JM, McGowan SJ, Roberts NA, Taylor S et al. 2016. Multiplexed analysis of chromosome conformation at vastly improved sensitivity. Nat. Methods 13:74–80
    [Google Scholar]
  40. 40.
    De Gobbi M, Viprakasit V, Hughes JR, Fisher C, Buckle VJ et al. 2006. A regulatory SNP causes a human transcriptional promoter. Science 312:1215–17Provided the first report of a de novo regulatory element causing heritable disease.
    [Google Scholar]
  41. 41.
    Dekker J, Rippe K, Dekker M, Kleckner N 2002. Capturing chromosome conformation. Science 295:1306–11Established the most widespread methodology for studying chromatin folding.
    [Google Scholar]
  42. 42.
    Doerfler PA, Feng R, Li Y, Palmer LE, Porter SN et al. 2021. Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin. Nat. Genet. 53:1177–86
    [Google Scholar]
  43. 43.
    Domcke S, Hill AJ, Daza RM, Cao J, O'Day DR et al. 2020. A human cell atlas of fetal chromatin accessibility. Science 370:eaba7612Presented the first whole-body atlas of single-cell chromatin accessibility.
    [Google Scholar]
  44. 44.
    Dorsett D, Krantz ID. 2009. On the molecular etiology of Cornelia de Lange syndrome. Ann. N.Y. Acad. Sci. 1151:22–37
    [Google Scholar]
  45. 45.
    Doudna JA, Charpentier E. 2014. The new frontier of genome engineering with CRISPR-Cas9. Science 346:1258096
    [Google Scholar]
  46. 46.
    Downes DJ, Beagrie RA, Gosden ME, Telenius J, Carpenter SJ et al. 2021. High-resolution targeted 3C interrogation of cis-regulatory element organization at genome-wide scale. Nat. Commun. 12:531
    [Google Scholar]
  47. 47.
    Downes DJ, Cross AR, Hua P, Roberts N, Schwessinger R et al. 2021. Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus. Nat. Genet. 53:1606–15
    [Google Scholar]
  48. 48.
    Dukler N, Gulko B, Huang Y-F, Siepel A. 2017. Is a super-enhancer greater than the sum of its parts?. Nat. Genet. 49:2–3
    [Google Scholar]
  49. 49.
    Ebert P, Audano PA, Zhu Q, Rodriguez-Martin B, Porubsky D et al. 2021. Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Science 372:eabf7117
    [Google Scholar]
  50. 50.
    Frangoul H, Altshuler D, Cappellini MD, Chen Y-S, Domm J et al. 2021. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N. Engl. J. Med. 384:252–60Described the first clinical application of genomic editing of an enhancer.
    [Google Scholar]
  51. 51.
    Franke M, Ibrahim DM, Andrey G, Schwarzer W, Heinrich V et al. 2016. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538:265–69
    [Google Scholar]
  52. 52.
    Fudenberg G, Kelley DR, Pollard KS 2020. Predicting 3D genome folding from DNA sequence with Akita. Nat. Methods 17:1111–17Published simultaneously with DeepC (163) as the first tools to predict chromatin folding from sequence.
    [Google Scholar]
  53. 53.
    Fulco CP, Munschauer M, Anyoha R, Munson G, Grossman SR et al. 2016. Systematic mapping of functional enhancer-promoter connections with CRISPR interference. Science 354:769–73
    [Google Scholar]
  54. 54.
    Fulco CP, Nasser J, Jones TR, Munson G, Bergman DT et al. 2019. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat. Genet. 51:1664–69
    [Google Scholar]
  55. 55.
    Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH et al. 2017. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551:464–71 Correction. 2018. Nature 559:E8
    [Google Scholar]
  56. 56.
    Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA et al. 2013. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154:442–51
    [Google Scholar]
  57. 57.
    Grosselin K, Durand A, Marsolier J, Poitou A, Marangoni E et al. 2019. High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer. Nat. Genet. 51:1060–66
    [Google Scholar]
  58. 58.
    Grosveld F, van Staalduinen J, Stadhouders R. 2021. Transcriptional regulation by (super)enhancers: from discovery to mechanisms. Annu. Rev. Genom. Hum. Genet. 22:127–46
    [Google Scholar]
  59. 59.
    Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C et al. 2017. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170:522–33.e15
    [Google Scholar]
  60. 60.
    Hanssen LLP, Kassouf MT, Oudelaar AM, Biggs D, Preece C et al. 2017. Tissue-specific CTCF–cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo. Nat. Cell Biol. 19:952–61
    [Google Scholar]
  61. 61.
    Hatton C, Wilkie A, Drysdale H, Wood W, Vickers M et al. 1990. α-Thalassemia caused by a large (62 kb) deletion upstream of the human α globin gene cluster. Blood 76:221–27
    [Google Scholar]
  62. 62.
    Hay D, Hughes JR, Babbs C, Davies JOJ, Graham BJ et al. 2016. Genetic dissection of the α-globin super-enhancer in vivo. Nat. Genet. 48:895–903
    [Google Scholar]
  63. 63.
    Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A et al. 2009. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459:108–12
    [Google Scholar]
  64. 64.
    Hilton IB, D'Ippolito AM, Vockley CM, Thakore PI, Crawford GE et al. 2015. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33:510–17
    [Google Scholar]
  65. 65.
    Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP et al. 2009. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. PNAS 106:9362–67
    [Google Scholar]
  66. 66.
    Hoogendijk C, Scholtz C, Pimstone S, Ehrenborg E, Kastelein JP et al. 2003. Allelic variation in the promoter region of the LDL receptor gene: analysis of an African-specific variant in the FP2 cis-acting regulatory element. Mol. Cell. Probes 17:175–81
    [Google Scholar]
  67. 67.
    Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A et al. 2013. TERT promoter mutations in familial and sporadic melanoma. Science 339:959–61
    [Google Scholar]
  68. 68.
    Hörnblad A, Bastide S, Langenfeld K, Langa F, Spitz F. 2021. Dissection of the Fgf8 regulatory landscape by in vivo CRISPR-editing reveals extensive intra- and inter-enhancer redundancy. Nat. Commun. 12:439
    [Google Scholar]
  69. 69.
    Hsieh THS, Fudenberg G, Goloborodko A, Rando OJ. 2016. Micro-C XL: assaying chromosome conformation from the nucleosome to the entire genome. Nat. Methods 13:1009–11
    [Google Scholar]
  70. 70.
    Hua P, Badat M, Hanssen LLP, Hentges LD, Crump N et al. 2021. Defining genome architecture at base-pair resolution. Nature 595:125–29Achieved unprecedented base-pair resolution of chromatin folding by capturing MNase 3C libraries.
    [Google Scholar]
  71. 71.
    Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. 2013. Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–59
    [Google Scholar]
  72. 72.
    Huang L, Jolly LA, Willis-Owen S, Gardner A, Kumar R et al. 2012. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am. J. Hum. Genet. 91:694–702
    [Google Scholar]
  73. 73.
    Huang Y-F, Gulko B, Siepel A. 2017. Fast, scalable prediction of deleterious noncoding variants from functional and population genomic data. Nat. Genet. 49:618–24
    [Google Scholar]
  74. 74.
    ICGC/TCGA Pan-Cancer Anal. Whole Genomes Consort. 2020. Pan-cancer analysis of whole genomes. Nature 578:82–93
    [Google Scholar]
  75. 75.
    Ioannidis NM, Davis JR, DeGorter MK, Larson NB, McDonnell SK et al. 2017. FIRE: functional inference of genetic variants that regulate gene expression. Bioinformatics 33:3895–901
    [Google Scholar]
  76. 76.
    Jang YJ, LaBella AL, Feeney TP, Braverman N, Tuchman M et al. 2018. Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene. Hum. Mutat. 39:527–36
    [Google Scholar]
  77. 77.
    Janssens DH, Meers MP, Wu SJ, Babaeva E, Meshinchi S et al. 2021. Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia. Nat. Genet. 53:1586–96
    [Google Scholar]
  78. 78.
    Janssens DH, Wu SJ, Sarthy JF, Meers MP, Myers CH et al. 2018. Automated in situ chromatin profiling efficiently resolves cell types and gene regulatory programs. Epigenet. Chromatin 11:74
    [Google Scholar]
  79. 79.
    Jin W, Tang Q, Wan M, Cui K, Zhang Y et al. 2015. Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples. Nature 528:142–46
    [Google Scholar]
  80. 80.
    Jindal GA, Farley EK. 2021. Enhancer grammar in development, evolution, and disease: dependencies and interplay. Dev. Cell 56:575–87
    [Google Scholar]
  81. 81.
    John A, Brylka H, Wiegreffe C, Simon R, Liu P et al. 2012. Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development. Development 139:1831–41
    [Google Scholar]
  82. 82.
    Kaya-Okur HS, Wu SJ, Codomo CA, Pledger ES, Bryson TD et al. 2019. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10:1930
    [Google Scholar]
  83. 83.
    Kearns NA, Pham H, Tabak B, Genga RM, Silverstein NJ et al. 2015. Functional annotation of native enhancers with a Cas9-histone demethylase fusion. Nat. Methods 12:401–3
    [Google Scholar]
  84. 84.
    Kelley DR, Snoek J, Rinn JL. 2016. Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks. Genome Res 26:990–99
    [Google Scholar]
  85. 85.
    Kempfer R, Pombo A. 2020. Methods for mapping 3D chromosome architecture. Nat. Rev. Genet. 21:207–26
    [Google Scholar]
  86. 86.
    Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI et al. 2007. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128:1231–45
    [Google Scholar]
  87. 87.
    Kinkley S, Helmuth J, Polansky JK, Dunkel I, Gasparoni G et al. 2016. reChIP-seq reveals widespread bivalency of H3K4me3 and H3K27me3 in CD4+ memory T cells. Nat. Commun. 7:12514
    [Google Scholar]
  88. 88.
    Kioussis D, Vanin E, DeLange T, Flavell RA, Grosveld FG. 1983. β-Globin gene inactivation by DNA translocation in γβ-thalassaemi. Nature 306:662–66
    [Google Scholar]
  89. 89.
    Kircher M, Xiong C, Martin B, Schubach M, Inoue F et al. 2019. Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. Nat. Commun. 10:3583
    [Google Scholar]
  90. 90.
    Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. 2016. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533:420–24
    [Google Scholar]
  91. 91.
    Krijger PHL, Geeven G, Bianchi V, Hilvering CRE, De Laat W. 2020. 4C-seq from beginning to end: a detailed protocol for sample preparation and data analysis. Methods 170:17–32
    [Google Scholar]
  92. 92.
    Kubo N, Ishii H, Xiong X, Bianco S, Meitinger F et al. 2021. Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation. Nat. Struct. Mol. Biol. 28:152–61
    [Google Scholar]
  93. 93.
    Kurth I, Klopocki E, Stricker S, van Oosterwijk J, Vanek S et al. 2009. Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia. Nat. Genet. 41:862–63
    [Google Scholar]
  94. 94.
    Kvon EZ, Zhu Y, Kelman G, Novak CS, Plajzer-Frick I et al. 2020. Comprehensive in vivo interrogation reveals phenotypic impact of human enhancer variants. Cell 180:1262–71.e15
    [Google Scholar]
  95. 95.
    Kwak H, Fuda NJ, Core LJ, Lis JT. 2013. Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science 339:950–53
    [Google Scholar]
  96. 96.
    Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y et al. 2018. The human transcription factors. Cell 172:650–65
    [Google Scholar]
  97. 97.
    Landrum MJ, Chitipiralla S, Brown GR, Chen C, Gu B et al. 2020. ClinVar: improvements to accessing data. Nucleic Acids Res 48:D835–44
    [Google Scholar]
  98. 98.
    Larke MSC, Schwessinger R, Nojima T, Telenius J, Beagrie RA et al. 2021. Enhancers predominantly regulate gene expression during differentiation via transcription initiation. Mol. Cell 81:983–97.e7
    [Google Scholar]
  99. 99.
    Laugsch M, Bartusel M, Rehimi R, Alirzayeva H, Karaolidou A et al. 2019. Modeling the pathological long-range regulatory effects of human structural variation with patient-specific hiPSCs. Cell Stem Cell 24:736–52.e12
    [Google Scholar]
  100. 100.
    Laurent JM, Pinglay S, Mitchell L, Brosh R. 2019. Probing the dark matter of the human genome with big DNA. Biochemistry 41:46–48
    [Google Scholar]
  101. 101.
    Lee PH, Lee C, Li X, Wee B, Dwivedi T, Daly M. 2018. Principles and methods of in-silico prioritization of non-coding regulatory variants. Hum. Genet. 137:15–30
    [Google Scholar]
  102. 102.
    Lettice LA, Williamson I, Wiltshire JH, Peluso S, Devenney PS et al. 2012. Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev. Cell 22:459–67
    [Google Scholar]
  103. 103.
    Li J, Woods SL, Healey S, Beesley J, Chen X et al. 2016. Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant. Am. J. Hum. Genet. 98:830–42
    [Google Scholar]
  104. 104.
    Li Y, Haarhuis JHI, Sedeño Cacciatore Á, Oldenkamp R, van Ruiten MS et al. 2020. The structural basis for cohesin-CTCF-anchored loops. Nature 578:472–76
    [Google Scholar]
  105. 105.
    Li Z, Schulz MH, Look T, Begemann M, Zenke M, Costa IG. 2019. Identification of transcription factor binding sites using ATAC-seq. Genome Biol 20:45
    [Google Scholar]
  106. 106.
    Lian J, HamediRad M, Hu S, Zhao H. 2017. Combinatorial metabolic engineering using an orthogonal tri-functional CRISPR system. Nat. Commun. 8:1688
    [Google Scholar]
  107. 107.
    Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T et al. 2009. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:289–93
    [Google Scholar]
  108. 108.
    Liebhaber SA, Griese EU, Weiss I, Cash FE, Ayyub H et al. 1990. Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster. PNAS 87:9431–35
    [Google Scholar]
  109. 109.
    Liskova P, Dudakova L, Evans CJ, Rojas Lopez KE, Pontikos N et al. 2018. Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. Am. J. Hum. Genet. 102:447–59
    [Google Scholar]
  110. 110.
    Lohan S, Spielmann M, Doelken SC, Flöttmann R, Muhammad F et al. 2014. Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome. Clin. Genet. 86:318–25
    [Google Scholar]
  111. 111.
    Long HK, Osterwalder M, Welsh IC, Hansen K, Davies JOJ et al. 2020. Loss of extreme long-range enhancers in human neural crest drives a craniofacial disorder. Cell Stem Cell 27:765–83.e14
    [Google Scholar]
  112. 112.
    Lu F, Liu Y, Inoue A, Suzuki T, Zhao K, Zhang Y. 2016. Establishing chromatin regulatory landscape during mouse preimplantation development. Cell 165:1375–88
    [Google Scholar]
  113. 113.
    Ludwig LS, Lareau CA, Bao EL, Nandakumar SK, Muus C et al. 2019. Transcriptional states and chromatin accessibility underlying human erythropoiesis. Cell Rep 27:3228–40.e7
    [Google Scholar]
  114. 114.
    Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F et al. 2015. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161:1012–25
    [Google Scholar]
  115. 115.
    Maeder ML, Linder SJ, Cascio VM, Fu Y, Ho QH, Joung JK. 2013. CRISPR RNA-guided activation of endogenous human genes. Nat. Methods 10:977–79
    [Google Scholar]
  116. 116.
    Mali P, Aach J, Stranges PB, Esvelt KM, Moosburner M et al. 2013. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat. Biotechnol. 31:833–38
    [Google Scholar]
  117. 117.
    Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A et al. 2014. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346:1373–77
    [Google Scholar]
  118. 118.
    Marques AC, Hughes J, Graham B, Kowalczyk MS, Higgs DR, Ponting CP. 2013. Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs. Genome Biol 14:R131
    [Google Scholar]
  119. 119.
    Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E et al. 2012. Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–95
    [Google Scholar]
  120. 120.
    McCarty NS, Graham AE, Studená L, Ledesma-Amaro R. 2020. Multiplexed CRISPR technologies for gene editing and transcriptional regulation. Nat. Commun. 11:1281
    [Google Scholar]
  121. 121.
    Métais J-Y, Doerfler PA, Mayuranathan T, Bauer DE, Fowler SC et al. 2019. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin. Blood Adv 3:3379–92
    [Google Scholar]
  122. 122.
    Mettananda S, Fisher CA, Hay D, Badat M, Quek L et al. 2017. Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia. Nat. Commun. 8:424
    [Google Scholar]
  123. 123.
    Mika KM, Li X, DeMayo FJ, Lynch VJ. 2018. An ancient fecundability-associated polymorphism creates a GATA2 binding site in a distal enhancer of HLA-F. Am. J. Hum. Genet. 103:509–21
    [Google Scholar]
  124. 124.
    Mitchell LA, McCulloch LH, Pinglay S, Berger H, Bosco N et al. 2021. De novo assembly and delivery to mouse cells of a 101 kb functional human gene. Genetics 218:iyab038
    [Google Scholar]
  125. 125.
    Monahan K, Horta A, Lomvardas S 2019. LHX2- and LDB1-mediated trans interactions regulate olfactory receptor choice. Nature 565:448–53. Described a trans-acting enhancer cluster that regulates the expression of olfactory genes.
    [Google Scholar]
  126. 126.
    Moorthy SD, Davidson S, Shchuka VM, Singh G, Malek-Gilani N et al. 2017. Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes. Genome Res 27:246–58
    [Google Scholar]
  127. 127.
    Muto Y, Wilson PC, Ledru N, Wu H, Dimke H et al. 2021. Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney. Nat. Commun. 12:2190
    [Google Scholar]
  128. 128.
    Nabet B, Roberts JM, Buckley DL, Paulk J, Dastjerdi S et al. 2018. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 14:431–41
    [Google Scholar]
  129. 129.
    Ngcungcu T, Oti M, Sitek JC, Haukanes BI, Linghu B et al. 2017. Duplicated enhancer region increases expression of CTSB and segregates with keratolytic winter erythema in South African and Norwegian families. Am. J. Hum. Genet. 100:737–50
    [Google Scholar]
  130. 130.
    Nikpay M, Goel A, Won HH, Hall LM, Willenborg C et al. 2015. A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47:1121–30
    [Google Scholar]
  131. 131.
    Nishimura K, Fukagawa T, Takisawa H, Kakimoto T, Kanemaki M. 2009. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Methods 6:917–22
    [Google Scholar]
  132. 132.
    Nurk S, Koren S, Rhie A, Rautiainen M, Bzikadze AV et al. 2022. The complete sequence of a human genome. Science 376:44–53
    [Google Scholar]
  133. 133.
    Osterwalder M, Barozzi I, Tissières V, Fukuda-Yuzawa Y, Mannion BJ et al. 2018. Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554:239–43
    [Google Scholar]
  134. 134.
    Oudelaar AM, Beagrie RA, Gosden M, de Ornellas S, Georgiades E et al. 2020. Dynamics of the 4D genome during in vivo lineage specification and differentiation. Nat. Commun. 11:2722
    [Google Scholar]
  135. 135.
    Oudelaar AM, Higgs DR. 2021. The relationship between genome structure and function. Nat. Rev. Genet. 22:154–68
    [Google Scholar]
  136. 136.
    Owens DDG, Caulder A, Frontera V, Harman JR, Allan AJ et al. 2019. Microhomologies are prevalent at Cas9-induced larger deletions. Nucleic Acids Res 47:7402–17
    [Google Scholar]
  137. 137.
    Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R et al. 2002. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32:650–54Presented the first GWAS to map the risk of myocardial infarction to polymorphic loci.
    [Google Scholar]
  138. 138.
    Paliou C, Guckelberger P, Schöpflin R, Heinrich V, Esposito A et al. 2019. Preformed chromatin topology assists transcriptional robustness of Shh during limb development. PNAS 116:12390–99
    [Google Scholar]
  139. 139.
    Pei G, Hu R, Dai Y, Manuel AM, Zhao Z, Jia P. 2021. Predicting regulatory variants using a dense epigenomic mapped CNN model elucidated the molecular basis of trait-tissue associations. Nucleic Acids Res 49:53–66
    [Google Scholar]
  140. 140.
    Pei G, Hu R, Jia P, Zhao Z. 2021. DeepFun: a deep learning sequence-based model to decipher non-coding variant effect in a tissue- and cell type-specific manner. Nucleic Acids Res 49:W131–39
    [Google Scholar]
  141. 141.
    Pennisi E. 2012. ENCODE Project writes eulogy for junk DNA. Science 337:1159–61
    [Google Scholar]
  142. 142.
    Pradeepa MM, Grimes GR, Kumar Y, Olley G, Taylor GCA et al. 2016. Histone H3 globular domain acetylation identifies a new class of enhancers. Nat. Genet. 48:681–86
    [Google Scholar]
  143. 143.
    Pugacheva EM, Kubo N, Loukinov D, Tajmul M, Kang S et al. 2020. CTCF mediates chromatin looping via N-terminal domain-dependent cohesin retention. PNAS 117:2020–31
    [Google Scholar]
  144. 144.
    Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS et al. 2013. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–83
    [Google Scholar]
  145. 145.
    Quang D, Xie X. 2016. DanQ: a hybrid convolutional and recurrent deep neural network for quantifying the function of DNA sequences. Nucleic Acids Res 44:e107
    [Google Scholar]
  146. 146.
    Radziwon A, Arno G, Wheaton DK, McDonagh EM, Baple EL et al. 2017. Single-base substitutions in the CHM promoter as a cause of choroideremia. Hum. Mutat. 38:704–15
    [Google Scholar]
  147. 147.
    Raffeiner P, Hart JR, García-Caballero D, Bar-Peled L, Weinberg MS, Vogt PK. 2020. An MXD1-derived repressor peptide identifies noncoding mediators of MYC-driven cell proliferation. PNAS 117:6571–79
    [Google Scholar]
  148. 148.
    Raffield LM, Ulirsch JC, Naik RP, Lessard S, Handsaker RE et al. 2018. Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease. PLOS Genet 14:e1007293
    [Google Scholar]
  149. 149.
    Rai V, Quang DX, Erdos MR, Cusanovich DA, Daza RM et al. 2020. Single-cell ATAC-Seq in human pancreatic islets and deep learning upscaling of rare cells reveals cell-specific type 2 diabetes regulatory signatures. Mol. Metab. 32:109–21
    [Google Scholar]
  150. 150.
    Roadmap Epigenom. Consort. Kundaje A, Meuleman W, Ernst J, Bilenky M et al. 2015. Integrative analysis of 111 reference human epigenomes. Nature 518:317–30
    [Google Scholar]
  151. 151.
    Rotem A, Ram O, Shoresh N, Sperling RA, Goren A et al. 2015. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat. Biotechnol. 33:1165–72
    [Google Scholar]
  152. 152.
    Rozenblatt-Rosen O, Shin JW, Rood JE, Hupalowska A, Regev A, Heyn H. 2021. Building a high-quality Human Cell Atlas. Nat. Biotechnol 39:149–53
    [Google Scholar]
  153. 153.
    Sander JD, Joung JK. 2014. CRISPR-Cas systems for editing, regulating and targeting genomes. Nat. Biotechnol. 32:347–55
    [Google Scholar]
  154. 154.
    Sanders AD, Falconer E, Hills M, Spierings DCJ, Lansdorp PM. 2017. Single-cell template strand sequencing by Strand-seq enables the characterization of individual homologs. Nat. Protoc. 12:1151–76
    [Google Scholar]
  155. 155.
    Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G et al. 2008. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322:1839–42
    [Google Scholar]
  156. 156.
    Satpathy AT, Granja JM, Yost KE, Qi Y, Meschi F et al. 2019. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat. Biotechnol. 37:925–36
    [Google Scholar]
  157. 157.
    Schmidl C, Rendeiro AF, Sheffield NC, Bock C. 2015. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat. Methods 12:963–65
    [Google Scholar]
  158. 158.
    Schmiedel BJ, Seumois G, Samaniego-Castruita D, Cayford J, Schulten V et al. 2016. 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nat. Commun. 7:13426
    [Google Scholar]
  159. 159.
    Scholtz CL, Peeters AV, Hoogendijk CF, Thiart R, de Villiers JNP et al. 1999. Mutation −59c→t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia. Hum. Mol. Genet. 8:2025–30
    [Google Scholar]
  160. 160.
    Schones DE, Cui K, Cuddapah S, Roh T-Y, Barski A et al. 2008. Dynamic regulation of nucleosome positioning in the human genome. Cell 132:887–98
    [Google Scholar]
  161. 161.
    Schwalb B, Michel M, Zacher B, Frühauf K, Demel C et al. 2016. TT-seq maps the human transient transcriptome. Science 352:1225–28
    [Google Scholar]
  162. 162.
    Schwartzman O, Mukamel Z, Oded-Elkayam N, Olivares-Chauvet P, Lubling Y et al. 2016. UMI-4C for quantitative and targeted chromosomal contact profiling. Nat. Methods 13:685–91
    [Google Scholar]
  163. 163.
    Schwessinger R, Gosden M, Downes D, Brown RC, Oudelaar AM et al. 2020. DeepC: predicting 3D genome folding using megabase-scale transfer learning. Nat. Methods 17:1118–24Published simultaneously with Akita (52) as the first tools to predict chromatin folding from sequence.
    [Google Scholar]
  164. 164.
    Schwessinger R, Suciu MC, Mcgowan SJ, Telenius J, Taylor S et al. 2017. Sasquatch: predicting the impact of regulatory SNPs on transcription factor binding from cell- and tissue-specific DNase footprints. Genome Res 27:1730–42
    [Google Scholar]
  165. 165.
    Shariati SA, Dominguez A, Xie S, Wernig M, Qi LS, Skotheim JM. 2019. Reversible disruption of specific transcription factor-DNA interactions using CRISPR/Cas9. Mol. Cell 74:622–33.e4
    [Google Scholar]
  166. 166.
    Shin HY, Willi M, Yoo KH, Zeng X, Wang C et al. 2016. Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat. Genet. 48:904–11
    [Google Scholar]
  167. 167.
    Skene PJ, Henikoff S 2017. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. eLife 6:e21856
    [Google Scholar]
  168. 168.
    Snetkova V, Ypsilanti AR, Akiyama JA, Mannion BJ, Plajzer-Frick I et al. 2021. Ultraconserved enhancer function does not require perfect sequence conservation. Nat. Genet. 53:521–28
    [Google Scholar]
  169. 169.
    Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC et al. 2016. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533:95–99
    [Google Scholar]
  170. 170.
    Soukup AA, Zheng Y, Mehta C, Wu J, Liu P et al. 2019. Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer. J. Clin. Investig. 129:1180–92
    [Google Scholar]
  171. 171.
    Tian J, Chang J, Gong J, Lou J, Fu M et al. 2019. Systematic functional interrogation of genes in GWAS loci identified ATF1 as a key driver in colorectal cancer modulated by a promoter-enhancer interaction. Am. J. Hum. Genet. 105:29–47
    [Google Scholar]
  172. 172.
    Ushiki A, Zhang Y, Xiong C, Zhao J, Georgakopoulos-Soares I et al. 2021. Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia. Nat. Commun. 12:2282
    [Google Scholar]
  173. 173.
    Wang A, Chiou J, Poirion OB, Buchanan J, Valdez MJ et al. 2020. Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes. eLife 9:e62522
    [Google Scholar]
  174. 174.
    Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY et al. 2013. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307–19
    [Google Scholar]
  175. 175.
    Will AJ, Cova G, Osterwalder M, Chan W-L, Wittler L et al. 2017. Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). Nat. Genet. 49:1539–45
    [Google Scholar]
  176. 176.
    Wright CF, FitzPatrick DR, Firth HV. 2018. Paediatric genomics: diagnosing rare disease in children. Nat. Rev. Genet. 19:253–68
    [Google Scholar]
  177. 177.
    Wright JB, Brown SJ, Cole MD. 2010. 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. 30:1411–20
    [Google Scholar]
  178. 178.
    Zhou J, Theesfeld CL, Yao K, Chen KM, Wong AK, Troyanskaya OG. 2018. Deep learning sequence-based ab initio prediction of variant effects on expression and disease risk. Nat. Genet. 50:1171–79
    [Google Scholar]
  179. 179.
    Zhou J, Troyanskaya OG. 2015. Predicting effects of noncoding variants with deep learning-based sequence model. Nat. Methods 12:931–34
    [Google Scholar]
  180. 180.
    Ziffra RS, Kim CN, Ross JM, Wilfert A, Turner TN et al. 2021. Single-cell epigenomics reveals mechanisms of human cortical development. Nature 598:205–13
    [Google Scholar]
/content/journals/10.1146/annurev-genom-112921-010715
Loading
/content/journals/10.1146/annurev-genom-112921-010715
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error