Abstract
Regulatory elements are the genomic regions that interact with transcription factors to control cell-type-specific gene expression in different cellular environments. A precise and complete catalog of functional elements encoded by the human genome is key to understanding mammalian gene regulation. Here, we review the current state of regulatory element annotation. We first provide an overview of assays for characterizing functional elements, including genome, epigenome, transcriptome, three-dimensional chromatin interaction, and functional validation assays. We then discuss computational methods for defining regulatory elements, including peak-calling and other statistical modeling methods. Finally, we introduce several high-quality lists of regulatory element annotations and suggest potential future directions.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All of the datasets discussed in this review are publicly available.
References
Akalin A, Fredman D, Arner E et al (2009) Transcriptional features of genomic regulatory blocks. Genome Biol 10:R38. https://doi.org/10.1186/gb-2009-10-4-r38
Alexander RP, Fang G, Rozowsky J et al (2010) Annotating non-coding regions of the genome. Nat Rev Genet 11:559–571. https://doi.org/10.1038/nrg2814
Alipanahi B, Delong A, Weirauch MT, Frey BJ (2015) Predicting the sequence specificities of DNA- and RNA-binding proteins by deep learning. Nat Biotechnol 33:831–838. https://doi.org/10.1038/nbt.3300
Altarejos JY, Montminy M (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12:141–151. https://doi.org/10.1038/nrm3072
Andersson R, Sandelin A (2020) Determinants of enhancer and promoter activities of regulatory elements. Nat Rev Genet 21:71–87. https://doi.org/10.1038/s41576-019-0173-8
Andersson R, Gebhard C, Miguel-Escalada I et al (2014) An atlas of active enhancers across human cell types and tissues. Nature 507:455–461. https://doi.org/10.1038/nature12787
Andersson R, Sandelin A, Danko CG (2015) A unified architecture of transcriptional regulatory elements. Trends Genet 31:426–433. https://doi.org/10.1016/j.tig.2015.05.007
Ardui S, Ameur A, Vermeesch JR, Hestand MS (2018) Single molecule real-time (SMRT) sequencing comes of age: applications and utilities for medical diagnostics. Nucleic Acids Res 46:2159–2168
Arnold CD, Gerlach D, Stelzer C et al (2013) Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339:1074–1077. https://doi.org/10.1126/science.1232542
Asthana S, Noble WS, Kryukov G et al (2007) Widely distributed noncoding purifying selection in the human genome. Proc Natl Acad Sci U S A 104:12410–12415. https://doi.org/10.1073/pnas.0705140104
Avsec Ž, Agarwal V, Visentin D et al (2021a) Effective gene expression prediction from sequence by integrating long-range interactions. Nat Methods 18:1196–1203. https://doi.org/10.1038/s41592-021-01252-x
Avsec Ž, Weilert M, Shrikumar A et al (2021b) Base-resolution models of transcription-factor binding reveal soft motif syntax. Nat Genet 53:354–366. https://doi.org/10.1038/s41588-021-00782-6
Bailey T, Krajewski P, Ladunga I et al (2013) Practical guidelines for the comprehensive analysis of ChIP-seq data. PLoS Comput Biol 9:e1003326. https://doi.org/10.1371/journal.pcbi.1003326
Banerji J, Olson L, Schaffner W (1983) A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell 33:729–740. https://doi.org/10.1016/0092-8674(83)90015-6
Batut P, Dobin A, Plessy C et al (2013) High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression. Genome Res 23:169–180. https://doi.org/10.1101/gr.139618.112
Baylin SB, Jones PA (2016) Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a019505
Beagrie RA, Scialdone A, Schueler M et al (2017) Complex multi-enhancer contacts captured by genome architecture mapping. Nature 543:519–524. https://doi.org/10.1038/nature21411
Becker JS, Nicetto D, Zaret KS (2016) H3K9me3-dependent heterochromatin: barrier to cell fate changes. Trends Genet 32:29–41. https://doi.org/10.1016/j.tig.2015.11.001
Becker JS, McCarthy RL, Sidoli S et al (2017) Genomic and proteomic resolution of heterochromatin and its restriction of alternate fate genes. Mol Cell 68:1023-1037.e15. https://doi.org/10.1016/j.molcel.2017.11.030
Bender CM, Gonzalgo ML, Gonzales FA et al (1999) Roles of cell division and gene transcription in the methylation of CpG islands. Mol Cell Biol 19:6690–6698. https://doi.org/10.1128/MCB.19.10.6690
Bernstein BE, Mikkelsen TS, Xie X et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326. https://doi.org/10.1016/j.cell.2006.02.041
Bird AP, Taggart MH (1980) Variable patterns of total DNA and rDNA methylation in animals. Nucleic Acids Res 8:1485–1497. https://doi.org/10.1093/nar/8.7.1485
Bird A, Taggart M, Frommer M et al (1985) A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40:91–99. https://doi.org/10.1016/0092-8674(85)90312-5
Blackwood EM, Kadonaga JT (1998) Going the distance: a current view of enhancer action. Science 281:60–63. https://doi.org/10.1126/science.281.5373.60
Boix CA, James BT, Park YP et al (2021) Regulatory genomic circuitry of human disease loci by integrative epigenomics. Nature 590:300–307. https://doi.org/10.1038/s41586-020-03145-z
Boyle AP, Davis S, Shulha HP et al (2008) High-resolution mapping and characterization of open chromatin across the genome. Cell 132:311–322. https://doi.org/10.1016/j.cell.2007.12.014
Buenrostro JD, Giresi PG, Zaba LC et al (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10:1213–1218. https://doi.org/10.1038/nmeth.2688
Buenrostro JD, Wu B, Litzenburger UM et al (2015) Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523:486–490. https://doi.org/10.1038/nature14590
Burley SK, Roeder RG (1996) Biochemistry and structural biology of transcription factor IID (TFIID). Annu Rev Biochem 65:769–799. https://doi.org/10.1146/annurev.bi.65.070196.004005
Cai Y, Zhang Y, Loh YP et al (2021) H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions. Nat Commun 12:719. https://doi.org/10.1038/s41467-021-20940-y
Carelli FN, Liechti A, Halbert J et al (2018) Repurposing of promoters and enhancers during mammalian evolution. Nat Commun 9:4066. https://doi.org/10.1038/s41467-018-06544-z
Carleton JB, Berrett KC, Gertz J (2017) Multiplex enhancer interference reveals collaborative control of gene regulation by estrogen receptor α-bound enhancers. Cell Syst 5:333-344.e5
Carninci P, Sandelin A, Lenhard B et al (2006) Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet 38:626–635. https://doi.org/10.1038/ng1789
Chan RCW, Libbrecht MW, Roberts EG et al (2018) Segway 2.0: Gaussian mixture models and minibatch training. Bioinformatics 34:669–671. https://doi.org/10.1093/bioinformatics/btx603
Chandra V, Bhattacharyya S, Schmiedel BJ et al (2021) Promoter-interacting expression quantitative trait loci are enriched for functional genetic variants. Nat Genet 53:110–119. https://doi.org/10.1038/s41588-020-00745-3
Chatterjee S, Ahituv N (2017) Gene regulatory elements, major drivers of human disease. Annu Rev Genomics Hum Genet 18:45–63. https://doi.org/10.1146/annurev-genom-091416-035537
Cheng Y, Wu W, Kumar SA et al (2009) Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression. Genome Res 19:2172–2184. https://doi.org/10.1101/gr.098921.109
Chiaromonte F, Weber RJ, Roskin KM et al (2003) The share of human genomic DNA under selection estimated from human-mouse genomic alignments. Cold Spring Harb Symp Quant Biol 68:245–254. https://doi.org/10.1101/sqb.2003.68.245
Chong JA, Tapia-Ramírez J, Kim S et al (1995) REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80:949–957. https://doi.org/10.1016/0092-8674(95)90298-8
Cooper DN, Krawczak M (1989) Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes. Hum Genet 83:181–188. https://doi.org/10.1007/BF00286715
Cooper GM, Stone EA, Asimenos G et al (2005) Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15:901–913. https://doi.org/10.1101/gr.3577405
Corces MR, Trevino AE, Hamilton EG et al (2017) An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods 14:959–962. https://doi.org/10.1038/nmeth.4396
Core LJ, Waterfall JJ, Lis JT (2008) Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322:1845–1848. https://doi.org/10.1126/science.1162228
Core LJ, Martins AL, Danko CG et al (2014) Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat Genet 46:1311–1320. https://doi.org/10.1038/ng.3142
Creyghton MP, Cheng AW, Welstead GG et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A 107:21931–21936. https://doi.org/10.1073/pnas.1016071107
Dao LTM, Galindo-Albarrán AO, Castro-Mondragon JA et al (2017) Genome-wide characterization of mammalian promoters with distal enhancer functions. Nat Genet 49:1073–1081. https://doi.org/10.1038/ng.3884
Davies JOJ, Oudelaar AM, Higgs DR, Hughes JR (2017) How best to identify chromosomal interactions: a comparison of approaches. Nat Methods 14:125–134. https://doi.org/10.1038/nmeth.4146
de Almeida BP, Reiter F, Pagani M, Stark A (2022) DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers. Nat Genet 54:613–624. https://doi.org/10.1038/s41588-022-01048-5
De Santa F, Barozzi I, Mietton F et al (2010) A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol 8:e1000384. https://doi.org/10.1371/journal.pbio.1000384
Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25:1010–1022. https://doi.org/10.1101/gad.2037511
Dekker J, Rippe K, Dekker M, Kleckner N (2002) Capturing chromosome conformation. Science 295:1306–1311. https://doi.org/10.1126/science.1067799
Diao Y, Fang R, Li B et al (2017) A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat Methods 14:629–635
Dixit A, Parnas O, Li B et al (2016) Perturb-Seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens. Cell 167:1853-1866.e17. https://doi.org/10.1016/j.cell.2016.11.038
Doni Jayavelu N, Jajodia A, Mishra A, Hawkins RD (2020) Candidate silencer elements for the human and mouse genomes. Nat Commun 11:1061. https://doi.org/10.1038/s41467-020-14853-5
Dostie J, Richmond TA, Arnaout RA et al (2006) Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res 16:1299–1309. https://doi.org/10.1101/gr.5571506
Driscoll MC, Dobkin CS, Alter BP (1989) Gamma delta beta-thalassemia due to a de novo mutation deleting the 5’ beta-globin gene activation-region hypersensitive sites. Proc Natl Acad Sci U S A 86:7470–7474. https://doi.org/10.1073/pnas.86.19.7470
Ehret CF, de Haller G (1963) Origin, development and maturation of organelles and organelle systems of the cell surface in paramecium. J Ultrastruct Res 23(SUPPL6):1–42. https://doi.org/10.1016/s0022-5320(63)80088-x
Elliott K, Larsson E (2021) Non-coding driver mutations in human cancer. Nat Rev Cancer 21:500–509. https://doi.org/10.1038/s41568-021-00371-z
Emorine L, Kuehl M, Weir L et al (1983) A conserved sequence in the immunoglobulin Jκ–Cκ intron: possible enhancer element. Nature 304:447–449. https://doi.org/10.1038/304447a0
ENCODE Project Consortium (2004) The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306:636–640. https://doi.org/10.1126/science.1105136
ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74. https://doi.org/10.1038/nature11247
ENCODE Project Consortium, Moore JE, Purcaro MJ et al (2020) Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583:699–710. https://doi.org/10.1038/s41586-020-2493-4
Epstein DJ (2009) Cis-regulatory mutations in human disease. Brief Funct Genom Proteom 8:310–316. https://doi.org/10.1093/bfgp/elp021
Ernst J, Kellis M (2010) Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol 28:817–825. https://doi.org/10.1038/nbt.1662
Ernst J, Kellis M (2012) ChromHMM: automating chromatin-state discovery and characterization. Nat Methods 9:215–216. https://doi.org/10.1038/nmeth.1906
Ernst J, Kellis M (2017) Chromatin-state discovery and genome annotation with ChromHMM. Nat Protoc 12:2478–2492. https://doi.org/10.1038/nprot.2017.124
Fan K, Moore JE, Zhang X-O, Weng Z (2021) Genetic and epigenetic features of promoters with ubiquitous chromatin accessibility support ubiquitous transcription of cell-essential genes. Nucleic Acids Res 49:5705–5725. https://doi.org/10.1093/nar/gkab345
Feng S, Cokus SJ, Zhang X et al (2010) Conservation and divergence of methylation patterning in plants and animals. Proc Natl Acad Sci USA 107:8689–8694. https://doi.org/10.1073/pnas.1002720107
Frankish A, Diekhans M, Ferreira A-M et al (2019) GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res 47:D766–D773. https://doi.org/10.1093/nar/gky955
Frankish A, Diekhans M, Jungreis I et al (2021) GENCODE 2021. Nucleic Acids Res 49:D916–D923. https://doi.org/10.1093/nar/gkaa1087
Frazer KA, Tao H, Osoegawa K et al (2004) Noncoding sequences conserved in a limited number of mammals in the SIM2 interval are frequently functional. Genome Res 14:367–372. https://doi.org/10.1101/gr.1961204
French JD, Edwards SL (2020) The role of noncoding variants in heritable disease. Trends Genet 36:880–891. https://doi.org/10.1016/j.tig.2020.07.004
Fu S, Wang Q, Moore JE et al (2018) Differential analysis of chromatin accessibility and histone modifications for predicting mouse developmental enhancers. Nucleic Acids Res 46:11184–11201. https://doi.org/10.1093/nar/gky753
Fuke C, Shimabukuro M, Petronis A et al (2004) Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet 68:196–204. https://doi.org/10.1046/j.1529-8817.2004.00081.x
Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261–282. https://doi.org/10.1016/0022-2836(87)90689-9
Gershenzon NI, Ioshikhes IP (2005) Synergy of human Pol II core promoter elements revealed by statistical sequence analysis. Bioinformatics 21:1295–1300. https://doi.org/10.1093/bioinformatics/bti172
Gillies SD, Morrison SL, Oi VT, Tonegawa S (1983) A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell 33:717–728. https://doi.org/10.1016/0092-8674(83)90014-4
Greenberg MVC, Bourc’his D (2019) The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol 20:590–607. https://doi.org/10.1038/s41580-019-0159-6
Greener JG, Kandathil SM, Moffat L, Jones DT (2022) A guide to machine learning for biologists. Nat Rev Mol Cell Biol 23:40–55. https://doi.org/10.1038/s41580-021-00407-0
Grice EA, Rochelle ES, Green ED et al (2005) Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer. Hum Mol Genet 14:3837–3845. https://doi.org/10.1093/hmg/ddi408
GTEx Consortium (2020) The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369:1318–1330. https://doi.org/10.1126/science.aaz1776
Haberle V, Stark A (2018) Eukaryotic core promoters and the functional basis of transcription initiation. Nat Rev Mol Cell Biol 19:621–637. https://doi.org/10.1038/s41580-018-0028-8
Haberle V, Arnold CD, Pagani M et al (2019) Transcriptional cofactors display specificity for distinct types of core promoters. Nature 570:122–126. https://doi.org/10.1038/s41586-019-1210-7
Hager GL, Sabo P, Thurman R et al (2009) Interaction of the glucocorticoid receptor with the chromatin landscape. FASEB J 23:487.3. https://doi.org/10.1096/fasebj.23.1_supplement.487.3
Hah N, Murakami S, Nagari A et al (2013) Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23:1210–1223. https://doi.org/10.1101/gr.152306.112
Hansen TJ, Hodges E (2022) ATAC-STARR-seq reveals transcription factor-bound activators and silencers across the chromatin accessible human genome. Genome Res. https://doi.org/10.1101/gr.276766.122
Hardison RC (2012) Genome-wide epigenetic data facilitate understanding of disease susceptibility association studies. J Biol Chem 287:30932–30940. https://doi.org/10.1074/jbc.R112.352427
Harrow J, Frankish A, Gonzalez JM et al (2012) GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res 22:1760–1774. https://doi.org/10.1101/gr.135350.111
He HH, Meyer CA, Hu SS et al (2014) Refined DNase-seq protocol and data analysis reveals intrinsic bias in transcription factor footprint identification. Nat Methods 11:73–78. https://doi.org/10.1038/nmeth.2762
He Y, Hariharan M, Gorkin DU et al (2020) Spatiotemporal DNA methylome dynamics of the developing mouse fetus. Nature 583:752–759. https://doi.org/10.1038/s41586-020-2119-x
Heintzman ND, Stuart RK, Hon G et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39:311–318. https://doi.org/10.1038/ng1966
Herz H-M, Hu D, Shilatifard A (2014) Enhancer malfunction in cancer. Mol Cell 53:859–866. https://doi.org/10.1016/j.molcel.2014.02.033
Hesselberth JR, Chen X, Zhang Z et al (2009) Global mapping of protein-DNA interactions in vivo by digital genomic footprinting. Nat Methods 6:283–289. https://doi.org/10.1038/nmeth.1313
Hindorff LA, Sethupathy P, Junkins HA et al (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106:9362–9367. https://doi.org/10.1073/pnas.0903103106
Hirabayashi S, Bhagat S, Matsuki Y et al (2019) NET-CAGE characterizes the dynamics and topology of human transcribed cis-regulatory elements. Nat Genet 51:1369–1379. https://doi.org/10.1038/s41588-019-0485-9
Hoffman MM, Buske OJ, Wang J et al (2012) Unsupervised pattern discovery in human chromatin structure through genomic segmentation. Nat Methods 9:473–476. https://doi.org/10.1038/nmeth.1937
Holliday R, Grigg GW (1993) DNA methylation and mutation. Mutat Res 285:61–67. https://doi.org/10.1016/0027-5107(93)90052-h
Holtzman L, Gersbach CA (2018) Editing the epigenome: reshaping the genomic landscape. Annu Rev Genomics Hum Genet 19:43–71. https://doi.org/10.1146/annurev-genom-083117-021632
Hon GC, Hawkins RD, Caballero OL et al (2012) Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res 22:246–258. https://doi.org/10.1101/gr.125872.111
Hsieh C-L, Fei T, Chen Y et al (2014) Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci USA 111:7319–7324. https://doi.org/10.1073/pnas.1324151111
Hsieh T-HS, Weiner A, Lajoie B et al (2015) Mapping nucleosome resolution chromosome folding in yeast by micro-C. Cell 162:108–119. https://doi.org/10.1016/j.cell.2015.05.048
Hsieh T-HS, Cattoglio C, Slobodyanyuk E et al (2020) Resolving the 3D landscape of transcription-linked mammalian chromatin folding. Mol Cell 78:539-553.e8. https://doi.org/10.1016/j.molcel.2020.03.002
Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157:1262–1278. https://doi.org/10.1016/j.cell.2014.05.010
Huang D, Ovcharenko I (2022) Enhancer–silencer transitions in the human genome. Genome Res 32:437–448. https://doi.org/10.1101/gr.275992.121
Huang D, Petrykowska HM, Miller BF et al (2019) Identification of human silencers by correlating cross-tissue epigenetic profiles and gene expression. Genome Res 29:657–667. https://doi.org/10.1101/gr.247007.118
International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–945. https://doi.org/10.1038/nature03001
Jeon H, Lee H, Kang B et al (2020) Comparative analysis of commonly used peak calling programs for ChIP-Seq analysis. Genom Inform 18:e42. https://doi.org/10.5808/GI.2020.18.4.e42
Jin Y, Eser U, Struhl K, Churchman LS (2017) The ground state and evolution of promoter region directionality. Cell 170:889-898.e10. https://doi.org/10.1016/j.cell.2017.07.006
Jing H, Vakoc CR, Ying L et al (2008) Exchange of GATA factors mediates transitions in looped chromatin organization at a developmentally regulated gene locus. Mol Cell 29:232–242. https://doi.org/10.1016/j.molcel.2007.11.020
Johnson DS, Davidson B, Brown CD et al (2004) Noncoding regulatory sequences of Ciona exhibit strong correspondence between evolutionary constraint and functional importance. Genome Res 14:2448–2456. https://doi.org/10.1101/gr.2964504
Johnson DS, Mortazavi A, Myers RM, Wold B (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316:1497–1502. https://doi.org/10.1126/science.1141319
Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492. https://doi.org/10.1038/nrg3230
Kadonaga JT (2012) Perspectives on the RNA polymerase II core promoter. Wiley Interdiscip Rev Dev Biol 1:40–51. https://doi.org/10.1002/wdev.21
Kelley DR, Snoek J, Rinn JL (2016) Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks. Genome Res 26:990–999. https://doi.org/10.1101/gr.200535.115
Kelley DR, Reshef YA, Bileschi M et al (2018) Sequential regulatory activity prediction across chromosomes with convolutional neural networks. Genome Res 28:739–750. https://doi.org/10.1101/gr.227819.117
Kellis M, Wold B, Snyder MP et al (2014) Defining functional DNA elements in the human genome. Proc Natl Acad Sci U S A 111:6131–6138. https://doi.org/10.1073/pnas.1318948111
Kichaev G, Pasaniuc B (2015) Leveraging functional-annotation data in trans-ethnic fine-mapping studies. Am J Hum Genet 97:260–271. https://doi.org/10.1016/j.ajhg.2015.06.007
Kichaev G, Yang W-Y, Lindstrom S et al (2014) Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet 10:e1004722. https://doi.org/10.1371/journal.pgen.1004722
Kim T-K, Hemberg M, Gray JM et al (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182–187. https://doi.org/10.1038/nature09033
Kim S, Yu N-K, Kaang B-K (2015) CTCF as a multifunctional protein in genome regulation and gene expression. Exp Mol Med 47:e166. https://doi.org/10.1038/emm.2015.33
Kioussis D, Vanin E, deLange T et al (1983) β-Globin gene inactivation by DNA translocation in γβ-thalassemia. Nature 306:662–666. https://doi.org/10.1038/306662a0
Kleinjan DJ, van Heyningen V (1998) Position effect in human genetic disease. Hum Mol Genet 7:1611–1618. https://doi.org/10.1093/hmg/7.10.1611
Klemm SL, Shipony Z, Greenleaf WJ (2019) Chromatin accessibility and the regulatory epigenome. Nat Rev Genet 20:207–220. https://doi.org/10.1038/s41576-018-0089-8
Koido M, Hon C-C, Koyama S et al (2022) Prediction of the cell-type-specific transcription of non-coding RNAs from genome sequences via machine learning. Nat Biomed Eng. https://doi.org/10.1038/s41551-022-00961-8
Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705. https://doi.org/10.1016/j.cell.2007.02.005
Krietenstein N, Abraham S, Venev SV et al (2020) Ultrastructural details of mammalian chromosome architecture. Mol Cell 78:554-565.e7. https://doi.org/10.1016/j.molcel.2020.03.003
Kruesi WS, Core LJ, Waters CT et al (2013) Condensin controls recruitment of RNA polymerase II to achieve nematode X-chromosome dosage compensation. Elife 2:e00808. https://doi.org/10.7554/eLife.00808
Kwak H, Fuda NJ, Core LJ, Lis JT (2013) Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science 339:950–953. https://doi.org/10.1126/science.1229386
Lambert SA, Jolma A, Campitelli LF et al (2018) The human transcription factors. Cell 172:650–665. https://doi.org/10.1016/j.cell.2018.01.029
Larsen F, Gundersen G, Lopez R, Prydz H (1992) CpG islands as gene markers in the human genome. Genomics 13:1095–1107. https://doi.org/10.1016/0888-7543(92)90024-m
Laurent L, Wong E, Li G et al (2010) Dynamic changes in the human methylome during differentiation. Genome Res 20:320–331. https://doi.org/10.1101/gr.101907.109
LeCun Y, Boser B, Denker JS et al (1989) Backpropagation applied to handwritten zip code recognition. Neural Comput 1:541–551. https://doi.org/10.1162/neco.1989.1.4.541
Lesurf R, Cotto KC, Wang G et al (2015) ORegAnno 3.0: a community-driven resource for curated regulatory annotation. Nucleic Acids Res 44:D126–D132. https://doi.org/10.1093/nar/gkv1203
Lettice LA, Heaney SJH, Purdie LA et al (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12:1725–1735. https://doi.org/10.1093/hmg/ddg180
Lev Maor G, Yearim A, Ast G (2015) The alternative role of DNA methylation in splicing regulation. Trends Genet 31:274–280. https://doi.org/10.1016/j.tig.2015.03.002
Leviyang S (2021) Interferon stimulated binding of ISRE is cell type specific and is predicted by homeostatic chromatin state. Cytokine X 3:100056. https://doi.org/10.1016/j.cytox.2021.100056
Li E, Zhang Y (2014) DNA methylation in mammals. Cold Spring Harb Perspect Biol 6:a019133. https://doi.org/10.1101/cshperspect.a019133
Li G, Ruan X, Auerbach RK et al (2012) Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148:84–98. https://doi.org/10.1016/j.cell.2011.12.014
Li W, Notani D, Ma Q et al (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498:516–520. https://doi.org/10.1038/nature12210
Li Y, Zheng H, Wang Q et al (2018) Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys. Genome Biol 19:18. https://doi.org/10.1186/s13059-018-1390-8
Liang D, Elwell AL, Aygün N et al (2021) Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation. Nat Neurosci 24:941–953. https://doi.org/10.1038/s41593-021-00858-w
Libbrecht MW, Rodriguez OL, Weng Z et al (2019) A unified encyclopedia of human functional DNA elements through fully automated annotation of 164 human cell types. Genome Biol 20:180. https://doi.org/10.1186/s13059-019-1784-2
Lieberman-Aiden E, van Berkum NL, Williams L et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:289–293. https://doi.org/10.1126/science.1181369
Lim CY, Santoso B, Boulay T et al (2004) The MTE, a new core promoter element for transcription by RNA polymerase II. Genes Dev 18:1606–1617. https://doi.org/10.1101/gad.1193404
Lindblad-Toh K, Garber M, Zuk O et al (2011) A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478:476–482. https://doi.org/10.1038/nature10530
Linzer N, Trumbull A, Nar R et al (2021) Regulation of RNA polymerase II transcription initiation and elongation by transcription factor TFII-I. Front Mol Biosci 8:681550. https://doi.org/10.3389/fmolb.2021.681550
Lister R, Pelizzola M, Dowen RH et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322. https://doi.org/10.1038/nature08514
Logsdon GA, Vollger MR, Eichler EE (2020) Long-read human genome sequencing and its applications. Nat Rev Genet 21:597–614. https://doi.org/10.1038/s41576-020-0236-x
Loots GG, Locksley RM, Blankespoor CM et al (2000) Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288:136–140. https://doi.org/10.1126/science.288.5463.136
Louder RK, He Y, López-Blanco JR et al (2016) Corrigendum: structure of promoter-bound TFIID and model of human pre-initiation complex assembly. Nature 536:112. https://doi.org/10.1038/nature17984
Magnuson B, Veloso A, Kirkconnell KS et al (2015) Identifying transcription start sites and active enhancer elements using BruUV-seq. Sci Rep 5:17978. https://doi.org/10.1038/srep17978
Manolio TA, Collins FS, Cox NJ et al (2009) Finding the missing heritability of complex diseases. Nature 461:747–753. https://doi.org/10.1038/nature08494
Marasca F, Bodega B, Orlando V (2018) How polycomb-mediated cell memory deals with a changing environment. BioEssays 40:1700137
Marco E, Meuleman W, Huang J et al (2017) Multi-scale chromatin state annotation using a hierarchical hidden Markov model. Nat Commun 8:15011. https://doi.org/10.1038/ncomms15011
Martowicz ML, Grass JA, Boyer ME et al (2005) Dynamic GATA factor interplay at a multicomponent regulatory region of the GATA-2 locus. J Biol Chem 280:1724–1732. https://doi.org/10.1074/jbc.M406038200
Maston GA, Evans SK, Green MR (2006) Transcriptional regulatory elements in the human genome. Annu Rev Genom Hum Genet 7:29–59. https://doi.org/10.1146/annurev.genom.7.080505.115623
Maunakea AK, Nagarajan RP, Bilenky M et al (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466:253–257. https://doi.org/10.1038/nature09165
Maunakea AK, Chepelev I, Cui K, Zhao K (2013) Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res 23:1256–1269. https://doi.org/10.1038/cr.2013.110
Maurano MT, Humbert R, Rynes E et al (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–1195
Mayer A, di Iulio J, Maleri S et al (2015) Native elongating transcript sequencing reveals human transcriptional activity at nucleotide resolution. Cell 161:541–554. https://doi.org/10.1016/j.cell.2015.03.010
Mayran A, Drouin J (2018) Pioneer transcription factors shape the epigenetic landscape. J Biol Chem 293:13795–13804. https://doi.org/10.1074/jbc.R117.001232
Melnikov A, Murugan A, Zhang X et al (2012) Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nat Biotechnol 30:271–277. https://doi.org/10.1038/nbt.2137
Mercola M, Wang XF, Olsen J, Calame K (1983) Transcriptional enhancer elements in the mouse immunoglobulin heavy chain locus. Science 221:663–665. https://doi.org/10.1126/science.6306772
Merkenschlager M, Nora EP (2016) CTCF and cohesin in genome folding and transcriptional gene regulation. Annu Rev Genom Hum Genet 17:17–43. https://doi.org/10.1146/annurev-genom-083115-022339
Mifsud B, Tavares-Cadete F, Young AN et al (2015) Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet 47:598–606. https://doi.org/10.1038/ng.3286
Miraldi ER, Chen X, Weirauch MT (2021) Deciphering cis-regulatory grammar with deep learning. Nat Genet 53:266–268
Mitsis T, Efthimiadou A, Bacopoulou F et al (2020) Transcription factors and evolution: an integral part of gene expression (Review). World Acad Sci J. https://doi.org/10.3892/wasj.2020.32
Molina N, Suter DM, Cannavo R et al (2013) Stimulus-induced modulation of transcriptional bursting in a single mammalian gene. Proc Natl Acad Sci U S A 110:20563–20568. https://doi.org/10.1073/pnas.1312310110
Moore JE, Zhang X-O, Elhajjajy SI et al (2022) Integration of high-resolution promoter profiling assays reveals novel, cell type-specific transcription start sites across 115 human cell and tissue types. Genome Res 32:389–402. https://doi.org/10.1101/gr.275723.121
Mouse Genome Sequencing Consortium, Waterston RH, Lindblad-Toh K et al (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562. https://doi.org/10.1038/nature01262
Nakamura M, Gao Y, Dominguez AA, Qi LS (2021) CRISPR technologies for precise epigenome editing. Nat Cell Biol 23:11–22. https://doi.org/10.1038/s41556-020-00620-7
Nasser J, Bergman DT, Fulco CP et al (2021) Genome-wide enhancer maps link risk variants to disease genes. Nature 593:238–243. https://doi.org/10.1038/s41586-021-03446-x
Neumayr C, Pagani M, Stark A, Arnold CD (2019) STARR-seq and UMI-STARR-seq: assessing enhancer activities for genome-wide-, high-, and low-complexity candidate libraries. Curr Protoc Mol Biol 128:e105. https://doi.org/10.1002/cpmb.105
Ngan CY, Wong CH, Tjong H et al (2020) Chromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development. Nat Genet 52:264–272. https://doi.org/10.1038/s41588-020-0581-x
Nguyen CT, Gonzales FA, Jones PA (2001) Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic Acids Res 29:4598–4606. https://doi.org/10.1093/nar/29.22.4598
Nicetto D, Zaret KS (2019) Role of H3K9me3 heterochromatin in cell identity establishment and maintenance. Curr Opin Genet Dev 55:1–10. https://doi.org/10.1016/j.gde.2019.04.013
Nikolov DB, Burley SK (1997) RNA polymerase II transcription initiation: a structural view. Proc Natl Acad Sci USA 94:15–22. https://doi.org/10.1073/pnas.94.1.15
O’Leary NA, Wright MW, Brister JR et al (2016) Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res 44:D733–D745. https://doi.org/10.1093/nar/gkv1189
Ogbourne S, Antalis TM (1998) Transcriptional control and the role of silencers in transcriptional regulation in eukaryotes. Biochem J 331(Pt 1):1–14. https://doi.org/10.1042/bj3310001
Ong C-T, Corces VG (2014) CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet 15:234–246. https://doi.org/10.1038/nrg3663
Palazzo AF, Gregory TR (2014) The case for junk DNA. PLoS Genet 10:e1004351. https://doi.org/10.1371/journal.pgen.1004351
Pang B, Snyder MP (2020) Systematic identification of silencers in human cells. Nat Genet 52:254–263. https://doi.org/10.1038/s41588-020-0578-5
Parelho V, Hadjur S, Spivakov M et al (2008) Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 132:422–433. https://doi.org/10.1016/j.cell.2008.01.011
Park PJ (2009) ChIP–seq: advantages and challenges of a maturing technology. Nat Rev Genet 10:669–680. https://doi.org/10.1038/nrg2641
Parker SCJ, Hansen L, Abaan HO et al (2009) Local DNA topography correlates with functional noncoding regions of the human genome. Science 324:389–392. https://doi.org/10.1126/science.1169050
Patikoglou GA, Kim JL, Sun L et al (1999) TATA element recognition by the TATA box-binding protein has been conserved throughout evolution. Genes Dev 13:3217–3230. https://doi.org/10.1101/gad.13.24.3217
Patwardhan RP, Hiatt JB, Witten DM et al (2012) Massively parallel functional dissection of mammalian enhancers in vivo. Nat Biotechnol 30:265–270. https://doi.org/10.1038/nbt.2136
Paulsen MT, Veloso A, Prasad J et al (2013) Coordinated regulation of synthesis and stability of RNA during the acute TNF-induced proinflammatory response. Proc Natl Acad Sci U S A 110:2240–2245. https://doi.org/10.1073/pnas.1219192110
Pennacchio LA, Ahituv N, Moses AM et al (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444:499–502. https://doi.org/10.1038/nature05295
Pennacchio LA, Bickmore W, Dean A et al (2013) Enhancers: five essential questions. Nat Rev Genet 14:288–295. https://doi.org/10.1038/nrg3458
Pheasant M, Mattick JS (2007) Raising the estimate of functional human sequences. Genome Res 17:1245–1253. https://doi.org/10.1101/gr.6406307
Phillips JE, Corces VG (2009) CTCF: master weaver of the genome. Cell 137:1194–1211. https://doi.org/10.1016/j.cell.2009.06.001
Pickar-Oliver A, Gersbach CA (2019) The next generation of CRISPR–Cas technologies and applications. Nat Rev Mol Cell Biol 20:490–507. https://doi.org/10.1038/s41580-019-0131-5
Pickrell JK (2014) Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am J Hum Genet 94:559–573. https://doi.org/10.1016/j.ajhg.2014.03.004
Ponjavic J, Lenhard B, Kai C et al (2006) Transcriptional and structural impact of TATA-initiation site spacing in mammalian core promoters. Genome Biol 7:R78. https://doi.org/10.1186/gb-2006-7-8-R78
Ponting CP, Hardison RC (2011) What fraction of the human genome is functional? Genome Res 21:1769–1776. https://doi.org/10.1101/gr.116814.110
Preissl S, Gaulton KJ, Ren B (2022) Characterizing cis-regulatory elements using single-cell epigenomics. Nat Rev Genet. https://doi.org/10.1038/s41576-022-00509-1
Pugazhenthi S, Wang M, Pham S et al (2011) Downregulation of CREB expression in Alzheimer’s brain and in Aβ-treated rat hippocampal neurons. Mol Neurodegener 6:60. https://doi.org/10.1186/1750-1326-6-60
Pulakanti K, Pinello L, Stelloh C et al (2013) Enhancer transcribed RNAs arise from hypomethylated, Tet-occupied genomic regions. Epigenetics 8:1303–1320. https://doi.org/10.4161/epi.26597
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. https://doi.org/10.1093/nar/gkw226
Quang D, Xie X (2019) FactorNet: A deep learning framework for predicting cell type specific transcription factor binding from nucleotide-resolution sequential data. Methods 166:40–47. https://doi.org/10.1016/j.ymeth.2019.03.020
Raab JR, Kamakaka RT (2010) Insulators and promoters: closer than we think. Nat Rev Genet 11:439–446. https://doi.org/10.1038/nrg2765
Rang FJ, Kloosterman WP, de Ridder J (2018) From squiggle to basepair: computational approaches for improving nanopore sequencing read accuracy. Genome Biol 19:90. https://doi.org/10.1186/s13059-018-1462-9
Rao SSP, Huntley MH, Durand NC et al (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159:1665–1680. https://doi.org/10.1016/j.cell.2014.11.021
Ravarani CNJ, Flock T, Chavali S et al (2020) Molecular determinants underlying functional innovations of TBP and their impact on transcription initiation. Nat Commun 11:2384. https://doi.org/10.1038/s41467-020-16182-z
Roadmap Epigenomics Consortium, Kundaje A, Meuleman W et al (2015) Integrative analysis of 111 reference human epigenomes. Nature 518:317–330. https://doi.org/10.1038/nature14248
Routhier E, Mozziconacci J (2022) Genomics enters the deep learning era. PeerJ 10:e13613. https://doi.org/10.7717/peerj.13613
Sanyal A, Lajoie BR, Jain G, Dekker J (2012) The long-range interaction landscape of gene promoters. Nature 489:109–113. https://doi.org/10.1038/nature11279
Sartorelli V, Lauberth SM (2020) Enhancer RNAs are an important regulatory layer of the epigenome. Nat Struct Mol Biol 27:521–528. https://doi.org/10.1038/s41594-020-0446-0
Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci USA 103:1412–1417. https://doi.org/10.1073/pnas.0510310103
Schep AN, Buenrostro JD, Denny SK et al (2015) Structured nucleosome fingerprints enable high-resolution mapping of chromatin architecture within regulatory regions. Genome Res 25:1757–1770. https://doi.org/10.1101/gr.192294.115
Schlesinger F, Smith AD, Gingeras TR et al (2013) De novo DNA demethylation and noncoding transcription define active intergenic regulatory elements. Genome Res 23:1601–1614. https://doi.org/10.1101/gr.157271.113
Schoenherr CJ, Anderson DJ (1995) The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267:1360–1363. https://doi.org/10.1126/science.7871435
Schoggins JW (2019) Interferon-stimulated genes: what do they all do? Annu Rev Virol 6:567–584. https://doi.org/10.1146/annurev-virology-092818-015756
Schwessinger R, Gosden M, Downes D et al (2020) DeepC: predicting 3D genome folding using megabase-scale transfer learning. Nat Methods 17:1118–1124. https://doi.org/10.1038/s41592-020-0960-3
Seale K, Horvath S, Teschendorff A et al (2022) Making sense of the ageing methylome. Nat Rev Genet 23:585–605. https://doi.org/10.1038/s41576-022-00477-6
Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861. https://doi.org/10.1146/annurev.biochem.68.1.821
Shukla S, Kavak E, Gregory M et al (2011) CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479:74–79. https://doi.org/10.1038/nature10442
Siegfried Z, Eden S, Mendelsohn M et al (1999) DNA methylation represses transcription in vivo. Nat Genet 22:203–206. https://doi.org/10.1038/9727
Silverman MN, Sternberg EM (2012) Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci 1261:55–63. https://doi.org/10.1111/j.1749-6632.2012.06633.x
Simeonov DR, Gowen BG, Boontanrart M et al (2017) Discovery of stimulation-responsive immune enhancers with CRISPR activation. Nature 549:111–115. https://doi.org/10.1038/nature23875
Sims RJ 3rd, Mandal SS, Reinberg D (2004) Recent highlights of RNA-polymerase-II-mediated transcription. Curr Opin Cell Biol 16:263–271. https://doi.org/10.1016/j.ceb.2004.04.004
Snetkova V, Ypsilanti AR, Akiyama JA et al (2021) Ultraconserved enhancer function does not require perfect sequence conservation. Nat Genet 53:521–528. https://doi.org/10.1038/s41588-021-00812-3
Snetkova V, Pennacchio LA, Visel A, Dickel DE (2022) Perfect and imperfect views of ultraconserved sequences. Nat Rev Genet 23:182–194. https://doi.org/10.1038/s41576-021-00424-x
Sohn K-A, Ho JWK, Djordjevic D et al (2015) hiHMM: Bayesian non-parametric joint inference of chromatin state maps. Bioinformatics 31:2066–2074. https://doi.org/10.1093/bioinformatics/btv117
Song H, Liu Y, Tan Y et al (2022) Recurrent non-coding somatic and germline WT1 variants converge to disrupt MYB binding in acute promyelocytic leukemia. Blood J Am Soc Hematol 140(10):1132–1144. https://doi.org/10.1182/blood.2021014945
Spitz F (2016) Gene regulation at a distance: from remote enhancers to 3D regulatory ensembles. Semin Cell Dev Biol 57:57–67. https://doi.org/10.1016/j.semcdb.2016.06.017
Stadler MB, Murr R, Burger L et al (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480:490–495. https://doi.org/10.1038/nature10716
Steven A, Friedrich M, Jank P et al (2020) What turns CREB on? And off? And why does it matter? Cell Mol Life Sci 77:4049–4067. https://doi.org/10.1007/s00018-020-03525-8
Su X-J, Shen B-D, Wang K et al (2022) Roles of the neuron-restrictive silencer factor in the pathophysiological process of the central nervous system. Front Cell Dev Biol 10:834620. https://doi.org/10.3389/fcell.2022.834620
Symmons O, Uslu VV, Tsujimura T et al (2014) Functional and topological characteristics of mammalian regulatory domains. Genome Res 24:390–400. https://doi.org/10.1101/gr.163519.113
Takahashi H, Lassmann T, Murata M, Carninci P (2012) 5’ end-centered expression profiling using cap-analysis gene expression and next-generation sequencing. Nat Protoc 7:542–561. https://doi.org/10.1038/nprot.2012.005
Thompson R, Chan C (2018) NRSF and its epigenetic effectors: new treatments for neurological disease. Brain Sci 8:226. https://doi.org/10.3390/brainsci8120226
Thurman RE, Rynes E, Humbert R et al (2012) The accessible chromatin landscape of the human genome. Nature 489:75–82. https://doi.org/10.1038/nature11232
Tippens ND, Liang J, Leung AK-Y et al (2020) Transcription imparts architecture, function and logic to enhancer units. Nat Genet 52:1067–1075. https://doi.org/10.1038/s41588-020-0686-2
Tiwari VK, McGarvey KM, Licchesi JDF et al (2008) PcG proteins, DNA methylation, and gene repression by chromatin looping. PLoS Biol 6:2911–2927. https://doi.org/10.1371/journal.pbio.0060306
Tsai P-F, Dell’Orso S, Rodriguez J et al (2018) A muscle-specific enhancer RNA mediates cohesin recruitment and regulates transcription in trans. Mol Cell 71:129-141.e8. https://doi.org/10.1016/j.molcel.2018.06.008
Tuan D, Kong S, Hu K (1992) Transcription of the hypersensitive site HS2 enhancer in erythroid cells. Proc Natl Acad Sci U S A 89:11219–11223. https://doi.org/10.1073/pnas.89.23.11219
Unnikrishnan A, Hadad N, Masser DR et al (2018) Revisiting the genomic hypomethylation hypothesis of aging. Ann N Y Acad Sci 1418:69–79. https://doi.org/10.1111/nyas.13533
van der Velde A, Fan K, Tsuji J et al (2021) Annotation of chromatin states in 66 complete mouse epigenomes during development. Commun Biol 4:239. https://doi.org/10.1038/s42003-021-01756-4
Varley KE, Gertz J, Bowling KM et al (2013) Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res 23:555–567. https://doi.org/10.1101/gr.147942.112
Visel A, Minovitsky S, Dubchak I, Pennacchio LA (2006) VISTA Enhancer Browser—a database of tissue-specific human enhancers. Nucleic Acids Res 35:D88–D92. https://doi.org/10.1093/nar/gkl822
Visel A, Prabhakar S, Akiyama JA et al (2008) Ultraconservation identifies a small subset of extremely constrained developmental enhancers. Nat Genet 40:158–160. https://doi.org/10.1038/ng.2007.55
Wang H, La Russa M, Qi LS (2016) CRISPR/Cas9 in genome editing and beyond. Annu Rev Biochem 85:227–264. https://doi.org/10.1146/annurev-biochem-060815-014607
Wang H, Xu J, Lazarovici P et al (2018) cAMP response element-binding protein (CREB): a possible signaling molecule link in the pathophysiology of schizophrenia. Front Mol Neurosci 11:255. https://doi.org/10.3389/fnmol.2018.00255
Weidemüller P, Kholmatov M, Petsalaki E, Zaugg JB (2021) Transcription factors: Bridge between cell signaling and gene regulation. Proteomics 21:e2000034. https://doi.org/10.1002/pmic.202000034
Weikum ER, Knuesel MT, Ortlund EA, Yamamoto KR (2017) Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol 18:159–174
Wendt KS, Yoshida K, Itoh T et al (2008) Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 451:796–801. https://doi.org/10.1038/nature06634
Whalen S, Schreiber J, Noble WS, Pollard KS (2022) Navigating the pitfalls of applying machine learning in genomics. Nat Rev Genet 23:169–181. https://doi.org/10.1038/s41576-021-00434-9
Wick RR, Judd LM, Holt KE (2018) Deepbinner: Demultiplexing barcoded Oxford Nanopore reads with deep convolutional neural networks. PLoS Comput Biol 14:e1006583. https://doi.org/10.1371/journal.pcbi.1006583
Wick RR, Judd LM, Holt KE (2019) Performance of neural network basecalling tools for Oxford Nanopore sequencing. Genome Biol 20:129. https://doi.org/10.1186/s13059-019-1727-y
Wilbanks EG, Facciotti MT (2010) Evaluation of algorithm performance in ChIP-seq peak detection. PLoS ONE 5:e11471. https://doi.org/10.1371/journal.pone.0011471
Wilson VL, Smith RA, Ma S, Cutler RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262:9948–9951
Woolfe A, Goodson M, Goode DK et al (2005) Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol 3:e7. https://doi.org/10.1371/journal.pbio.0030007
Wu X, Sharp PA (2013) Divergent transcription: a driving force for new gene origination? Cell 155:990–996. https://doi.org/10.1016/j.cell.2013.10.048
Wyman D, Balderrama-Gutierrez G, Reese F et al (2020) A technology-agnostic long-read analysis pipeline for transcriptome discovery and quantification. bioRxiv 672931
Yang J, Corces VG (2011) Chromatin insulators: a role in nuclear organization and gene expression. Adv Cancer Res 110:43–76. https://doi.org/10.1016/B978-0-12-386469-7.00003-7
Yao L, Berman BP, Farnham PJ (2015) Demystifying the secret mission of enhancers: linking distal regulatory elements to target genes. Crit Rev Biochem Mol Biol 50:550–573. https://doi.org/10.3109/10409238.2015.1087961
Yao L, Liang J, Ozer A et al (2022) A comparison of experimental assays and analytical methods for genome-wide identification of active enhancers. Nat Biotechnol 40:1056–1065. https://doi.org/10.1038/s41587-022-01211-7
Yin Y, Morgunova E, Jolma A et al (2017) Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. https://doi.org/10.1126/science.aaj2239
Yuan H, Kelley DR (2022) scBasset: sequence-based modeling of single-cell ATAC-seq using convolutional neural networks. Nat Methods. https://doi.org/10.1038/s41592-022-01562-8
Zabidi MA, Stark A (2016) Regulatory enhancer–core-promoter communication via transcription factors and cofactors. Trends Genet 32:801–814. https://doi.org/10.1016/j.tig.2016.10.003
Zaret KS (2020) Pioneer Transcription factors initiating gene network changes. Annu Rev Genet 54:367–385. https://doi.org/10.1146/annurev-genet-030220-015007
Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25:2227–2241. https://doi.org/10.1101/gad.176826.111
Zemach A, McDaniel IE, Silva P, Zilberman D (2010) Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 328:916–919. https://doi.org/10.1126/science.1186366
Zhang Y, Mahony S (2019) Direct prediction of regulatory elements from partial data without imputation. PLoS Comput Biol 15:e1007399. https://doi.org/10.1371/journal.pcbi.1007399
Zhang Y, Liu T, Meyer CA et al (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9:R137. https://doi.org/10.1186/gb-2008-9-9-r137
Zhang Y, Wu W, Cheng Y et al (2009) Primary sequence and epigenetic determinants of in vivo occupancy of genomic DNA by GATA1. Nucleic Acids Res 37:7024–7038. https://doi.org/10.1093/nar/gkp747
Zhang F, Wen Y, Guo X (2014) CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum Mol Genet 23:R40–R46. https://doi.org/10.1093/hmg/ddu125
Zhang Y, An L, Yue F, Hardison RC (2016) Jointly characterizing epigenetic dynamics across multiple human cell types. Nucleic Acids Res 44:6721–6731. https://doi.org/10.1093/nar/gkw278
Zhao Z, Tavoosidana G, Sjölinder M et al (2006) Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nat Genet 38:1341–1347. https://doi.org/10.1038/ng1891
Zhou J, Troyanskaya OG (2015) Predicting effects of noncoding variants with deep learning–based sequence model. Nat Methods 12:931–934. https://doi.org/10.1038/nmeth.3547
Zhu Y, Sun L, Chen Z et al (2013) Predicting enhancer transcription and activity from chromatin modifications. Nucleic Acids Res 41:10032–10043. https://doi.org/10.1093/nar/gkt826
Funding
This work was supported by NIH Grant HG012343 to Zhiping Weng.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. KF performed the literature search and drafted the first draft of the manuscript. EP edited the manuscript and made critical improvements to the writing. KF and ZW revised the work.
Corresponding author
Ethics declarations
Conflict of interest
Financial interests: The authors Kaili Fan and Edith Pfister declare they have no financial interests. Non-financial interests: the author Zhiping Weng co-founded Rgenta Therapeutics, and she serves as a scientific advisor for the company and is a member of its board.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Fan, K., Pfister, E. & Weng, Z. Toward a comprehensive catalog of regulatory elements. Hum. Genet. 142, 1091–1111 (2023). https://doi.org/10.1007/s00439-023-02519-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-023-02519-3