981:
859:), with one member of the dimer anchored to its binding motif on the enhancer and the other member anchored to its binding motif on the promoter (represented by the red zigzags in the illustration). Several cell function specific transcription factor proteins (in 2018 Lambert et al. indicated there were about 1,600 transcription factors in a human cell) generally bind to specific motifs on an enhancer and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern the level of transcription of the target gene.
414:
113:
769:
992:(DNA-PKcs, KU70, KU80 and DNA LIGASE IV) (see figure). These enzymes repair the double-strand breaks within about 15 minutes to 2 hours. The double-strand breaks in the promoter are thus associated with TOP2B and at least these four repair enzymes. These proteins are present simultaneously on a single promoter nucleosome (there are about 147 nucleotides in the DNA sequence wrapped around a single nucleosome) located near the transcription start site of their target gene.
885:
625:
344:
926:. These MBD proteins have both a methyl-CpG-binding domain and a transcriptional repression domain. They bind to methylated DNA and guide or direct protein complexes with chromatin remodeling and/or histone modifying activity to methylated CpG islands. MBD proteins generally repress local chromatin by means such as catalyzing the introduction of repressive histone marks or creating an overall repressive chromatin environment through
25:
995:
The double-strand break introduced by TOP2B apparently frees the part of the promoter at an RNA polymeraseβbound transcription start site to physically move to its associated enhancer. This allows the enhancer, with its bound transcription factors and mediator proteins, to directly interact with the
947:
While only small amounts of EGR1 protein are detectable in cells that are un-stimulated, EGR1 translation into protein at one hour after stimulation is markedly elevated. Expression of EGR1 in various types of cells can be stimulated by growth factors, neurotransmitters, hormones, stress and injury.
943:
is a transcription factor important for regulation of methylation of CpG islands. An EGR1 transcription factor binding site is frequently located in enhancer or promoter sequences. There are about 12,000 binding sites for EGR1 in the mammalian genome and about half of EGR1 binding sites are located
936:
are proteins that bind to specific DNA sequences in order to regulate the expression of a given gene. The binding sequence for a transcription factor in DNA is usually about 10 or 11 nucleotides long. There are approximately 1,400 different transcription factors encoded in the human genome and they
846:
are sequences of the genome that are major gene-regulatory elements. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes. In a study of brain cortical neurons, 24,937 loops
871:
may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of a transcription factor bound to an enhancer in the illustration). An activated enhancer begins transcription of its RNA before activating a
956:
the methylated CpG islands at those promoters. Upon demethylation, these promoters can then initiate transcription of their target genes. Hundreds of genes in neurons are differentially expressed after neuron activation through EGR1 recruitment of TET1 to methylated regulatory sequences in their
804:
shown by a small red star on a transcription factor on the enhancer) the enhancer is activated and can now activate its target promoter. The active enhancer is transcribed on each strand of DNA in opposite directions by bound RNAP IIs. Mediator (a complex consisting of about 26 proteins in an
999:
Similarly, topoisomerase I (TOP1) enzymes appear to be located at many enhancers, and those enhancers become activated when TOP1 introduces a single-strand break. TOP1 causes single-strand breaks in particular enhancer DNA regulatory sequences when signaled by a specific enhancer-binding
866:
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in the Figure. An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the
847:
were found, bringing enhancers to promoters. Multiple enhancers, each often at tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control expression of their common target gene.
740:(mRNA) molecules, where they are used to control mRNA biogenesis or translation. A variety of biological molecules may bind to the RNA to accomplish this regulation, including proteins (e.g., translational repressors and splicing factors), other RNA molecules (e.g.,
919:. About 59% of promoter sequences have a CpG island while only about 6% of enhancer sequences have a CpG island. CpG islands constitute regulatory sequences, since if CpG islands are methylated in the promoter of a gene this can reduce or silence gene expression.
915:). About 28 million CpG dinucleotides occur in the human genome. In most tissues of mammals, on average, 70% to 80% of CpG cytosines are methylated (forming 5-methyl-CpG, or 5-mCpG). Methylated cytosines within CpG sequences often occur in groups, called
980:
863:(a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (RNAP II) enzyme bound to the promoter.
937:
constitute about 6% of all human protein coding genes. About 94% of transcription factor binding sites that are associated with signal-responsive genes occur in enhancers while only about 6% of such sites occur in promoters.
850:
The schematic illustration in this section shows an enhancer looping around to come into close physical proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of
1000:
transcription factor. Topoisomerase I breaks are associated with different DNA repair factors than those surrounding TOP2B breaks. In the case of TOP1, the breaks are associated most immediately with DNA repair enzymes
717:), while activators facilitate formation of a productive complex. Furthermore, DNA motifs have been shown to be predictive of epigenomic modifications, suggesting that transcription factors play a role in regulating the
795:
of the gene. The loop is stabilized by one architectural protein anchored to the enhancer and one anchored to the promoter and these proteins are joined to form a dimer (red zigzags). Specific regulatory
922:
DNA methylation regulates gene expression through interaction with methyl binding domain (MBD) proteins, such as MeCP2, MBD1 and MBD2. These MBD proteins bind most strongly to highly methylated
816:
that are located in DNA regions distant from the promoters of genes can have very large effects on gene expression, with some genes undergoing up to 100-fold increased expression due to such a
2614:
Jang WG, Kim EJ, Park KG, Park YB, Choi HS, Kim HJ, et al. (January 2007). "Glucocorticoid receptor mediated repression of human insulin gene expression is regulated by PGC-1alpha".
977:
is carried out in a mouse, this conditioning causes hundreds of gene-associated DSBs in the medial prefrontal cortex and hippocampus, which are important for learning and memory.
2427:
Ju BG, Lunyak VV, Perissi V, Garcia-Bassets I, Rose DW, Glass CK, Rosenfeld MG (June 2006). "A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription".
911:
marker found predominantly on cytosines within CpG dinucleotides, which consist of a cytosine is followed by a guanine reading in the 5β² to 3β² direction along the DNA strand (
760:
A regulatory DNA sequence does not regulate unless it is activated. Different regulatory sequences are activated and then implement their regulation by different mechanisms.
800:
bind to DNA sequence motifs on the enhancer. General transcription factors bind to the promoter. When a transcription factor is activated by a signal (here indicated as
948:
In the brain, when neurons are activated, EGR1 proteins are upregulated, and they bind to (recruit) pre-existing TET1 enzymes, which are highly expressed in neurons.
2684:
413:
112:
952:
can catalyze demethylation of 5-methylcytosine. When EGR1 transcription factors bring TET1 enzymes to EGR1 binding sites in promoters, the TET enzymes can
969:(TOP2B) for activation. The induction of particular double-strand breaks is specific with respect to the inducing signal. When neurons are activated
2052:
Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM (April 2009). "A census of human transcription factors: function, expression and evolution".
965:
About 600 regulatory sequences in promoters and about 800 regulatory sequences in enhancers appear to depend on double-strand breaks initiated by
1009:
944:
in promoters and half in enhancers. The binding of EGR1 to its target DNA binding site is insensitive to cytosine methylation in the DNA.
1196:
984:
Regulatory sequence in a promoter at a transcription start site with a paused RNA polymerase and a TOP2B-induced double-strand break
377:
277:
2534:"A comparative analysis of relative occurrence of transcription factor binding sites in vertebrate genomes and gene promoter areas"
2215:"Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations"
1287:
Whitaker JW, Zhao Chen, Wei Wang. (2014) Predicting the Human
Epigenome from DNA Motifs. Nature Methods. doi:10.1038/nmeth.3065
809:
Expression of genes in mammals can be upregulated when signals are transmitted to the promoters associated with the genes.
2851:
2670:
1178:
1021:
89:
805:
interacting structure) communicates regulatory signals from the enhancer DNA-bound transcription factors to the promoter.
56:
52:
2677:
2780:
1114:
989:
1785:"Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems"
1687:"The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription"
2856:
1400:
Spitz F, Furlong EE (September 2012). "Transcription factors: from enhancer binding to developmental control".
694:
661:
557:
373:
228:
2262:"Pausing sites of RNA polymerase II on actively transcribed genes are enriched in DNA double-stranded breaks"
1446:
Schoenfelder S, Fraser P (August 2019). "Long-range enhancer-promoter contacts in gene expression control".
1191:
792:
768:
2826:
2821:
2816:
2805:
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2790:
2785:
2770:
1161:
1156:
1151:
1140:
1130:
1125:
1120:
1104:
860:
810:
606:
316:
2810:
2800:
2775:
1145:
1135:
1109:
933:
837:
729:
698:
669:
645:
592:
585:
578:
571:
550:
393:
361:
295:
221:
1736:"MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300"
1302:"Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression"
1783:
Carullo NV, Phillips Iii RA, Simon RC, Soto SA, Hinds JE, Salisbury AJ, et al. (September 2020).
2693:
2436:
2378:
2115:
868:
833:
797:
702:
1685:
Mikhaylichenko O, Bondarenko V, Harnett D, Schor IE, Males M, Viales RR, Furlong EE (January 2018).
1216:
888:
A methyl group is added on the carbon at the number 5 position of the ring to form 5-methylcytosine
843:
829:
825:
776:
714:
665:
657:
649:
508:
480:
473:
466:
458:
450:
443:
369:
365:
200:
193:
186:
178:
150:
143:
135:
2460:
2242:
2077:
1881:
Jabbari K, Bernardi G (May 2004). "Cytosine methylation and CpG, TpG (CpA) and TpA frequencies".
1471:
1425:
1211:
1183:
1038:
653:
501:
494:
286:
164:
884:
2367:"Profiling DNA break sites and transcriptional changes in response to contextual fear learning"
2213:
Dellino GI, Palluzzi F, Chiariello AM, Piccioni R, Bianco S, Furia L, et al. (June 2019).
2104:"EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity"
2631:
2596:
2555:
2514:
2452:
2406:
2347:
2293:
2234:
2195:
2141:
2069:
2034:
1988:
1947:
1898:
1863:
1814:
1765:
1716:
1667:
1615:
1561:
1520:
1463:
1417:
1382:
1331:
1270:
974:
953:
836:
and tethering elements. Among this constellation of sequences, enhancers and their associated
788:
37:
1489:
Weintraub AS, Li CH, Zamudio AV, Sigova AA, Hannett NM, Day DS, et al. (December 2017).
2623:
2586:
2545:
2504:
2496:
2444:
2396:
2386:
2337:
2329:
2283:
2273:
2226:
2185:
2175:
2131:
2123:
2061:
2024:
1978:
1937:
1929:
1890:
1853:
1845:
1804:
1796:
1755:
1747:
1706:
1698:
1657:
1649:
1605:
1595:
1551:
1510:
1502:
1455:
1409:
1372:
1362:
1321:
1313:
1260:
1206:
996:
RNA polymerase that had been paused at the transcription start site to start transcription.
892:
2752:
2742:
2737:
1085:
1075:
1070:
1059:
801:
745:
85:
1300:
Beagan JA, Pastuzyn ED, Fernandez LR, Guo MH, Feng K, Titus KR, et al. (June 2020).
2440:
2382:
2260:
Singh S, Szlachta K, Manukyan A, Raimer HM, Dinda M, Bekiranov S, Wang YH (March 2020).
2119:
1538:
Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. (February 2018).
988:
Such TOP2B-induced double-strand breaks are accompanied by at least four enzymes of the
2509:
2484:
2401:
2366:
2342:
2317:
2288:
2261:
2190:
2164:"Genome-wide investigation of in vivo EGR-1 binding sites in monocytic differentiation"
2163:
2136:
2103:
1942:
1917:
1858:
1833:
1809:
1784:
1711:
1686:
1662:
1637:
1610:
1583:
1515:
1490:
1377:
1350:
1326:
1301:
1173:
1024:
often contain regulatory regions, and so they are often the subject of these analyses.
710:
1760:
1735:
736:, or transcriptional termination. Regulatory sequences are frequently associated with
2845:
2727:
2464:
2316:
Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, et al. (June 2015).
2246:
1475:
1429:
1053:
784:
737:
2550:
2533:
2318:"Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes"
1918:"Pervasive and CpG-dependent promoter-like characteristics of transcribed enhancers"
973:, just 22 TOP2B-induced double-strand breaks occur in their genomes. However, when
2762:
2214:
2081:
1584:"Positional specificity of different transcription factor classes within enhancers"
1097:
1005:
749:
733:
81:
1734:
Li QJ, Yang SH, Maeda Y, Sladek FM, Sharrocks AD, Martins-Green M (January 2003).
2391:
775:. An active enhancer regulatory sequence of DNA is enabled to interact with the
2717:
2162:
Kubosaki A, Tomaru Y, Tagami M, Arner E, Miura H, Suzuki T, et al. (2009).
1043:
949:
908:
896:
630:
529:
522:
309:
207:
45:
2627:
2500:
2333:
2127:
1894:
1588:
Proceedings of the
National Academy of Sciences of the United States of America
1556:
1539:
1506:
2591:
2574:
2230:
1582:
Grossman SR, Engreitz J, Ray JP, Nguyen TH, Hacohen N, Lander ES (July 2018).
1459:
1367:
1317:
927:
713:
from forming a productive complex with the transcriptional initiation region (
706:
543:
536:
349:
214:
41:
2278:
2180:
1274:
2712:
2485:"Ligand-dependent enhancer activation regulated by topoisomerase-I activity"
2448:
1834:"DNA methylation in human epigenomes depends on local topology of CpG sites"
1600:
1265:
1248:
1033:
912:
718:
2635:
2600:
2559:
2518:
2483:
Puc J, Kozbial P, Li W, Tan Y, Liu Z, Suter T, et al. (January 2015).
2456:
2410:
2351:
2297:
2238:
2199:
2145:
2073:
2038:
1992:
1951:
1902:
1867:
1818:
1769:
1751:
1720:
1702:
1671:
1619:
1565:
1524:
1467:
1421:
1386:
1335:
701:) that activate or inhibit transcription. Transcription factors may act as
389:
385:
1933:
1800:
2722:
2707:
1849:
1224:
1048:
1028:
923:
916:
904:
741:
697:). It is accomplished through the sequence-specific binding of proteins (
515:
487:
302:
171:
157:
1351:"The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1"
2662:
2102:
Sun Z, Xu X, He J, Murray A, Sun MA, Wei X, et al. (August 2019).
1983:
1966:
1020:
Genomes can be analyzed systematically to identify regulatory regions.
613:
332:
16:
Segment of nucleic acid that affects the expression of associated genes
2029:
2012:
1201:
1001:
633:
422:
381:
270:
263:
2065:
1653:
1413:
384:(light grey) and add a 5' cap and poly-A tail (dark grey). The mRNA
2747:
1080:
1065:
966:
767:
2830:
940:
852:
780:
690:
637:
624:
599:
353:
343:
323:
256:
249:
242:
2666:
2657:
2013:"Methyl-CpG-binding domain proteins: readers of the epigenome"
900:
873:
856:
725:
693:
expression normally happens at the level of RNA biosynthesis (
686:
564:
235:
18:
2532:
Stepanova M, Tiazhelova T, Skoblov M, Baranova A (May 2005).
1638:"The Mediator complex: a central integrator of transcription"
728:, regulation may occur at the level of protein biosynthesis (
92:
is an essential feature of all living organisms and viruses.
1916:
Steinhaus R, Gonzalez T, Seelow D, Robinson PN (June 2020).
1349:
Verheul TC, van Hijfte L, Perenthaler E, Barakat TS (2020).
23:
2652:
1491:"YY1 Is a Structural Regulator of Enhancer-Promoter Loops"
840:
have a leading role in the regulation of gene expression.
84:
molecule which is capable of increasing or decreasing the
1832:
LΓΆvkvist C, Dodd IB, Sneppen K, Haerter JO (June 2016).
783:
by formation of a chromosome loop. This can initiate
990:
non-homologous end joining (NHEJ) DNA repair pathway
404:
103:
2761:
2700:
2616:
360:controls when and where expression occurs for the
644:controls when expression occurs for the multiple
1967:"DNA methylation patterns and epigenetic memory"
1242:
1240:
872:promoter to initiate transcription of messenger
2658:ReMap - database of transcriptional regulators
2653:ORegAnno - Open Regulatory Annotation Database
1577:
1575:
1441:
1439:
709:, or both. Repressors often act by preventing
2678:
2573:Melloul D, Marshak S, Cerasi E (March 2002).
2311:
2309:
2307:
961:Activation by double- or single-strand breaks
8:
2011:Du Q, Luu PL, Stirzaker C, Clark SJ (2015).
1631:
1629:
2157:
2155:
1355:Frontiers in Cell and Developmental Biology
1249:"Eukaryotic and prokaryotic gene structure"
2685:
2671:
2663:
2575:"Regulation of insulin gene transcription"
2590:
2549:
2508:
2400:
2390:
2341:
2287:
2277:
2189:
2179:
2135:
2028:
1982:
1941:
1857:
1808:
1759:
1710:
1661:
1609:
1599:
1555:
1514:
1376:
1366:
1325:
1264:
930:remodeling and chromatin reorganization.
1295:
1293:
979:
883:
880:CpG island methylation and demethylation
2097:
2095:
2093:
2091:
1236:
791:(RNAP II) bound to the promoter at the
2478:
2476:
2474:
1642:Nature Reviews. Molecular Cell Biology
779:DNA regulatory sequence of its target
773:Regulation of transcription in mammals
764:Enhancer activation and implementation
593:Protein coding region
586:Protein coding region
565:DNA
271:Intron
264:Intron
257:Exon
250:Exon
243:Exon
236:DNA
88:of specific genes within an organism.
2422:
2420:
2365:Stott RT, Kritsky O, Tsai LH (2021).
2006:
2004:
2002:
392:untranslated regions (blue) regulate
376:of the gene into a pre-mRNA which is
7:
1247:Shafee, Thomas; Lowe, Rohan (2017).
310:Poly-A tail
303:5'cap
296:Protein coding region
1636:Allen BL, Taatjes DJ (March 2015).
1197:Open Regulatory Annotation Database
664:of the gene into an mRNA. The mRNA
614:Protein
600:mRNA
333:Protein
14:
1540:"The Human Transcription Factors"
672:into the final protein products.
623:
412:
342:
111:
396:into the final protein product.
1022:Conserved non-coding sequences
824:-regulatory sequences include
660:regions (yellow) regulate the
372:regions (yellow) regulate the
1:
2551:10.1093/bioinformatics/bti307
1179:Regulation of gene expression
1096:Regulatory sequences for the
838:transcription factor proteins
756:Activation and implementation
90:Regulation of gene expression
2392:10.1371/journal.pone.0249691
975:contextual fear conditioning
820:-regulatory sequence. These
516:3'UTR
488:5'UTR
437:Regulatory sequence
430:Regulatory sequence
289:mRNA
172:3'UTR
165:Open reading frame
158:5'UTR
129:Regulatory sequence
122:Regulatory sequence
2781:negative regulatory element
1115:negative regulatory element
2873:
2628:10.1016/j.bbrc.2006.11.074
2501:10.1016/j.cell.2014.12.023
2334:10.1016/j.cell.2015.05.032
2128:10.1038/s41467-019-11905-3
1895:10.1016/j.gene.2004.02.043
1557:10.1016/j.cell.2018.01.029
1507:10.1016/j.cell.2017.11.008
907:(see figure). 5-mC is an
57:the image placement policy
36:may require adjustment of
2592:10.1007/s00125-001-0728-y
2231:10.1038/s41588-019-0421-z
1460:10.1038/s41576-019-0128-0
1368:10.3389/fcell.2020.592164
1318:10.1038/s41593-020-0634-6
814:-regulatory DNA sequences
2279:10.1074/jbc.RA119.011665
2181:10.1186/gb-2009-10-4-r41
2054:Nature Reviews. Genetics
1448:Nature Reviews. Genetics
1402:Nature Reviews. Genetics
793:transcription start site
59:for further information.
2449:10.1126/science.1127196
1971:Genes & Development
1965:Bird A (January 2002).
1691:Genes & Development
1601:10.1073/pnas.1804663115
1253:WikiJournal of Medicine
1192:Gene regulatory network
1922:Nucleic Acids Research
1838:Nucleic Acids Research
1789:Nucleic Acids Research
1703:10.1101/gad.308619.117
985:
889:
876:from its target gene.
861:Mediator (coactivator)
806:
646:protein coding regions
34:This article's images
28:
2811:CAAT enhancer binding
2801:cAMP response element
2108:Nature Communications
1266:10.15347/wjm/2017.002
1146:CAAT enhancer binding
1136:cAMP response element
983:
934:Transcription factors
887:
798:transcription factors
771:
699:transcription factors
362:protein coding region
27:
2852:Regulatory sequences
2694:Regulatory sequences
1752:10.1093/emboj/cdg028
1501:(7): 1573β1588.e28.
869:transcription factor
787:(mRNA) synthesis by
666:untranslated regions
423:Polycistronic operon
278:Post-transcriptional
53:the picture tutorial
2441:2006Sci...312.1798J
2383:2021PLoSO..1649691S
2120:2019NatCo..10.3892S
1934:10.1093/nar/gkaa223
1801:10.1093/nar/gkaa671
1594:(30): E7222βE7230.
1306:Nature Neuroscience
642:Regulatory sequence
629:The structure of a
358:Regulatory sequence
348:The structure of a
326:mRNA
78:regulatory sequence
2435:(5781): 1798β802.
1984:10.1101/gad.947102
1850:10.1093/nar/gkw124
1039:Operator (biology)
986:
890:
807:
636:of protein-coding
80:is a segment of a
29:
2839:
2838:
2272:(12): 3990β4000.
2030:10.2217/epi.15.39
1928:(10): 5306β5317.
1795:(17): 9550β9570.
789:RNA polymerase II
748:, in the case of
732:), RNA cleavage,
683:
682:
679:
678:
403:
402:
74:
73:
2864:
2687:
2680:
2673:
2664:
2640:
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2611:
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2512:
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2424:
2415:
2414:
2404:
2394:
2362:
2356:
2355:
2345:
2313:
2302:
2301:
2291:
2281:
2257:
2251:
2250:
2225:(6): 1011β1023.
2210:
2204:
2203:
2193:
2183:
2159:
2150:
2149:
2139:
2099:
2086:
2085:
2049:
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2032:
2008:
1997:
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1962:
1956:
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1823:
1822:
1812:
1780:
1774:
1773:
1763:
1740:The EMBO Journal
1731:
1725:
1724:
1714:
1682:
1676:
1675:
1665:
1633:
1624:
1623:
1613:
1603:
1579:
1570:
1569:
1559:
1535:
1529:
1528:
1518:
1486:
1480:
1479:
1443:
1434:
1433:
1397:
1391:
1390:
1380:
1370:
1346:
1340:
1339:
1329:
1297:
1288:
1285:
1279:
1278:
1268:
1244:
1207:DNA binding site
967:topoisomerase 2Ξ²
893:5-Methylcytosine
689:, regulation of
668:(blue) regulate
627:
626:
616:
609:
602:
595:
588:
581:
574:
567:
560:
553:
546:
539:
532:
525:
518:
511:
504:
497:
490:
483:
476:
469:
461:
453:
446:
439:
432:
425:
416:
405:
346:
345:
335:
328:
319:
312:
305:
298:
291:
282:
273:
266:
259:
252:
245:
238:
231:
224:
217:
210:
203:
196:
189:
181:
174:
167:
160:
153:
146:
138:
131:
124:
115:
104:
100:
99:
69:
66:
60:
26:
19:
2872:
2871:
2867:
2866:
2865:
2863:
2862:
2861:
2857:Gene expression
2842:
2841:
2840:
2835:
2757:
2696:
2691:
2649:
2644:
2643:
2613:
2612:
2608:
2572:
2571:
2567:
2531:
2530:
2526:
2482:
2481:
2472:
2426:
2425:
2418:
2377:(7): e0249691.
2364:
2363:
2359:
2328:(7): 1592β605.
2315:
2314:
2305:
2259:
2258:
2254:
2219:Nature Genetics
2212:
2211:
2207:
2161:
2160:
2153:
2101:
2100:
2089:
2066:10.1038/nrg2538
2051:
2050:
2046:
2010:
2009:
2000:
1964:
1963:
1959:
1915:
1914:
1910:
1880:
1879:
1875:
1844:(11): 5123β32.
1831:
1830:
1826:
1782:
1781:
1777:
1733:
1732:
1728:
1684:
1683:
1679:
1654:10.1038/nrm3951
1635:
1634:
1627:
1581:
1580:
1573:
1537:
1536:
1532:
1488:
1487:
1483:
1445:
1444:
1437:
1414:10.1038/nrg3207
1399:
1398:
1394:
1348:
1347:
1343:
1299:
1298:
1291:
1286:
1282:
1246:
1245:
1238:
1233:
1187:-acting element
1170:
1094:
1060:Polyadenylation
1018:
963:
882:
802:phosphorylation
766:
758:
746:small molecules
675:
674:
673:
628:
620:
619:
618:
617:
612:
610:
605:
603:
598:
596:
591:
589:
584:
582:
577:
575:
570:
568:
563:
561:
556:
554:
549:
547:
542:
540:
535:
533:
528:
526:
521:
519:
514:
512:
507:
505:
500:
498:
493:
491:
486:
484:
479:
477:
472:
470:
464:
462:
456:
454:
449:
447:
442:
440:
435:
433:
428:
426:
421:
417:
399:
398:
397:
352:protein-coding
347:
339:
338:
337:
336:
331:
329:
325:
322:
320:
315:
313:
308:
306:
301:
299:
294:
292:
288:
285:
283:
279:
276:
274:
269:
267:
262:
260:
255:
253:
248:
246:
241:
239:
234:
232:
227:
225:
220:
218:
213:
211:
206:
204:
199:
197:
192:
190:
184:
182:
177:
175:
170:
168:
163:
161:
156:
154:
149:
147:
141:
139:
134:
132:
127:
125:
120:
116:
98:
70:
64:
61:
50:
38:image placement
30:
24:
17:
12:
11:
5:
2870:
2868:
2860:
2859:
2854:
2844:
2843:
2837:
2836:
2834:
2833:
2824:
2819:
2814:
2808:
2803:
2798:
2793:
2788:
2783:
2778:
2773:
2767:
2765:
2759:
2758:
2756:
2755:
2750:
2745:
2740:
2735:
2730:
2725:
2720:
2715:
2710:
2704:
2702:
2698:
2697:
2692:
2690:
2689:
2682:
2675:
2667:
2661:
2660:
2655:
2648:
2647:External links
2645:
2642:
2641:
2606:
2565:
2544:(9): 1789β96.
2538:Bioinformatics
2524:
2470:
2416:
2357:
2303:
2252:
2205:
2168:Genome Biology
2151:
2087:
2044:
2023:(6): 1051β73.
1998:
1957:
1908:
1873:
1824:
1775:
1726:
1677:
1625:
1571:
1550:(4): 650β665.
1530:
1481:
1454:(8): 437β455.
1435:
1392:
1341:
1312:(6): 707β717.
1289:
1280:
1235:
1234:
1232:
1229:
1228:
1227:
1222:
1220:-acting factor
1214:
1209:
1204:
1199:
1194:
1189:
1181:
1176:
1174:Regulator gene
1169:
1166:
1165:
1164:
1159:
1154:
1149:
1143:
1138:
1133:
1128:
1123:
1118:
1112:
1107:
1093:
1090:
1089:
1088:
1083:
1078:
1073:
1068:
1063:
1057:
1051:
1046:
1041:
1036:
1031:
1017:
1014:
962:
959:
881:
878:
765:
762:
757:
754:
711:RNA polymerase
681:
680:
677:
676:
622:
621:
611:
604:
597:
590:
583:
576:
569:
562:
555:
548:
541:
534:
527:
520:
513:
506:
499:
492:
485:
478:
471:
463:
455:
448:
441:
434:
427:
420:
419:
418:
411:
410:
409:
408:
401:
400:
341:
340:
330:
321:
314:
307:
300:
293:
284:
275:
268:
261:
254:
247:
240:
233:
226:
219:
212:
205:
198:
191:
183:
176:
169:
162:
155:
148:
140:
133:
126:
119:
118:
117:
110:
109:
108:
107:
97:
94:
72:
71:
33:
31:
22:
15:
13:
10:
9:
6:
4:
3:
2:
2869:
2858:
2855:
2853:
2850:
2849:
2847:
2832:
2828:
2825:
2823:
2820:
2818:
2815:
2812:
2809:
2807:
2804:
2802:
2799:
2797:
2794:
2792:
2789:
2787:
2784:
2782:
2779:
2777:
2774:
2772:
2769:
2768:
2766:
2764:
2760:
2754:
2751:
2749:
2746:
2744:
2741:
2739:
2736:
2734:
2731:
2729:
2728:SECIS element
2726:
2724:
2721:
2719:
2716:
2714:
2711:
2709:
2706:
2705:
2703:
2699:
2695:
2688:
2683:
2681:
2676:
2674:
2669:
2668:
2665:
2659:
2656:
2654:
2651:
2650:
2646:
2637:
2633:
2629:
2625:
2622:(3): 716β21.
2621:
2617:
2610:
2607:
2602:
2598:
2593:
2588:
2585:(3): 309β26.
2584:
2580:
2576:
2569:
2566:
2561:
2557:
2552:
2547:
2543:
2539:
2535:
2528:
2525:
2520:
2516:
2511:
2506:
2502:
2498:
2495:(3): 367β80.
2494:
2490:
2486:
2479:
2477:
2475:
2471:
2466:
2462:
2458:
2454:
2450:
2446:
2442:
2438:
2434:
2430:
2423:
2421:
2417:
2412:
2408:
2403:
2398:
2393:
2388:
2384:
2380:
2376:
2372:
2368:
2361:
2358:
2353:
2349:
2344:
2339:
2335:
2331:
2327:
2323:
2319:
2312:
2310:
2308:
2304:
2299:
2295:
2290:
2285:
2280:
2275:
2271:
2267:
2263:
2256:
2253:
2248:
2244:
2240:
2236:
2232:
2228:
2224:
2220:
2216:
2209:
2206:
2201:
2197:
2192:
2187:
2182:
2177:
2173:
2169:
2165:
2158:
2156:
2152:
2147:
2143:
2138:
2133:
2129:
2125:
2121:
2117:
2113:
2109:
2105:
2098:
2096:
2094:
2092:
2088:
2083:
2079:
2075:
2071:
2067:
2063:
2060:(4): 252β63.
2059:
2055:
2048:
2045:
2040:
2036:
2031:
2026:
2022:
2018:
2014:
2007:
2005:
2003:
1999:
1994:
1990:
1985:
1980:
1976:
1972:
1968:
1961:
1958:
1953:
1949:
1944:
1939:
1935:
1931:
1927:
1923:
1919:
1912:
1909:
1904:
1900:
1896:
1892:
1888:
1884:
1877:
1874:
1869:
1865:
1860:
1855:
1851:
1847:
1843:
1839:
1835:
1828:
1825:
1820:
1816:
1811:
1806:
1802:
1798:
1794:
1790:
1786:
1779:
1776:
1771:
1767:
1762:
1757:
1753:
1749:
1746:(2): 281β91.
1745:
1741:
1737:
1730:
1727:
1722:
1718:
1713:
1708:
1704:
1700:
1696:
1692:
1688:
1681:
1678:
1673:
1669:
1664:
1659:
1655:
1651:
1648:(3): 155β66.
1647:
1643:
1639:
1632:
1630:
1626:
1621:
1617:
1612:
1607:
1602:
1597:
1593:
1589:
1585:
1578:
1576:
1572:
1567:
1563:
1558:
1553:
1549:
1545:
1541:
1534:
1531:
1526:
1522:
1517:
1512:
1508:
1504:
1500:
1496:
1492:
1485:
1482:
1477:
1473:
1469:
1465:
1461:
1457:
1453:
1449:
1442:
1440:
1436:
1431:
1427:
1423:
1419:
1415:
1411:
1408:(9): 613β26.
1407:
1403:
1396:
1393:
1388:
1384:
1379:
1374:
1369:
1364:
1360:
1356:
1352:
1345:
1342:
1337:
1333:
1328:
1323:
1319:
1315:
1311:
1307:
1303:
1296:
1294:
1290:
1284:
1281:
1276:
1272:
1267:
1262:
1258:
1254:
1250:
1243:
1241:
1237:
1230:
1226:
1223:
1221:
1219:
1215:
1213:
1210:
1208:
1205:
1203:
1200:
1198:
1195:
1193:
1190:
1188:
1186:
1182:
1180:
1177:
1175:
1172:
1171:
1167:
1163:
1160:
1158:
1155:
1153:
1150:
1147:
1144:
1142:
1139:
1137:
1134:
1132:
1129:
1127:
1124:
1122:
1119:
1116:
1113:
1111:
1108:
1106:
1103:
1102:
1101:
1099:
1091:
1087:
1084:
1082:
1079:
1077:
1074:
1072:
1069:
1067:
1064:
1061:
1058:
1055:
1054:SECIS element
1052:
1050:
1047:
1045:
1042:
1040:
1037:
1035:
1032:
1030:
1027:
1026:
1025:
1023:
1015:
1013:
1011:
1007:
1003:
997:
993:
991:
982:
978:
976:
972:
968:
960:
958:
955:
951:
945:
942:
938:
935:
931:
929:
925:
920:
918:
914:
910:
906:
902:
898:
894:
886:
879:
877:
875:
870:
864:
862:
858:
854:
848:
845:
841:
839:
835:
831:
827:
823:
819:
815:
813:
803:
799:
794:
790:
786:
785:messenger RNA
782:
778:
774:
770:
763:
761:
755:
753:
751:
747:
743:
739:
738:messenger RNA
735:
731:
727:
722:
720:
716:
712:
708:
704:
700:
696:
695:transcription
692:
688:
671:
667:
663:
662:transcription
659:
655:
651:
647:
643:
639:
635:
632:
615:
608:
601:
594:
587:
580:
579:RBS
573:
572:RBS
566:
559:
558:Transcription
552:
545:
538:
531:
524:
517:
510:
503:
496:
489:
482:
475:
468:
460:
452:
445:
438:
431:
424:
415:
407:
406:
395:
391:
387:
383:
379:
375:
374:transcription
371:
367:
363:
359:
355:
351:
334:
327:
318:
311:
304:
297:
290:
281:
272:
265:
258:
251:
244:
237:
230:
229:Transcription
223:
216:
209:
202:
195:
188:
180:
173:
166:
159:
152:
145:
137:
130:
123:
114:
106:
105:
102:
101:
95:
93:
91:
87:
83:
79:
68:
65:February 2022
58:
54:
49:
47:
43:
39:
32:
21:
20:
2763:Insulin gene
2732:
2619:
2615:
2609:
2582:
2579:Diabetologia
2578:
2568:
2541:
2537:
2527:
2492:
2488:
2432:
2428:
2374:
2370:
2360:
2325:
2321:
2269:
2265:
2255:
2222:
2218:
2208:
2171:
2167:
2111:
2107:
2057:
2053:
2047:
2020:
2016:
1974:
1970:
1960:
1925:
1921:
1911:
1886:
1882:
1876:
1841:
1837:
1827:
1792:
1788:
1778:
1743:
1739:
1729:
1697:(1): 42β57.
1694:
1690:
1680:
1645:
1641:
1591:
1587:
1547:
1543:
1533:
1498:
1494:
1484:
1451:
1447:
1405:
1401:
1395:
1358:
1354:
1344:
1309:
1305:
1283:
1256:
1252:
1217:
1184:
1098:insulin gene
1095:
1092:Insulin gene
1062:signal, mRNA
1019:
998:
994:
987:
970:
964:
946:
939:
932:
921:
899:form of the
895:(5-mC) is a
891:
865:
849:
842:
821:
817:
811:
808:
772:
759:
750:riboswitches
734:RNA splicing
723:
684:
641:
436:
429:
357:
280:modification
128:
121:
82:nucleic acid
77:
75:
62:
35:
2718:Pribnow box
2266:J Biol Chem
2114:(1): 3892.
2017:Epigenomics
1977:(1): 6β21.
1044:Pribnow box
957:promoters.
954:demethylate
950:TET enzymes
924:CpG islands
917:CpG islands
730:translation
670:translation
631:prokaryotic
607:Translation
394:translation
317:Translation
96:Description
51:Please see
2846:Categories
2174:(4): R41.
1361:: 592164.
1231:References
928:nucleosome
909:epigenetic
897:methylated
834:insulators
707:repressors
703:activators
551:Terminator
544:Stop
537:Stop
530:Start
523:Start
380:to remove
350:eukaryotic
222:Terminator
215:Stop
208:Start
201:Core
194:Proximal
86:expression
42:formatting
2713:CCAAT box
2465:206508330
2247:159041612
1889:: 143β9.
1476:152283312
1430:205485256
1275:2002-4436
1034:CCAAT box
913:CpG sites
844:Enhancers
830:silencers
826:enhancers
719:epigenome
2723:TATA box
2708:CAAT box
2636:17150186
2601:11914736
2560:15699025
2519:25619691
2457:16794079
2411:34197463
2371:PLOS ONE
2352:26052046
2298:32029477
2239:31110352
2200:19374776
2146:31467272
2074:19274049
2039:25927341
1993:11782440
1952:32338759
1903:15177689
1868:26932361
1819:32810208
1770:12514134
1721:29378788
1672:25693131
1620:29987030
1566:29425488
1525:29224777
1468:31086298
1422:22868264
1387:33102493
1336:32451484
1225:ORegAnno
1212:Promoter
1168:See also
1049:TATA box
1029:CAAT box
1016:Examples
971:in vitro
905:cytosine
777:promoter
715:promoter
658:enhancer
654:operator
650:Promoter
509:UTR
502:ORF
495:ORF
481:Promoter
474:Operator
467:silencer
459:silencer
451:Enhancer
444:Enhancer
378:modified
370:enhancer
366:Promoter
187:silencer
179:Enhancer
151:Promoter
144:silencer
136:Enhancer
2701:General
2510:4422651
2437:Bibcode
2429:Science
2402:8248687
2379:Bibcode
2343:4886855
2289:7086017
2191:2688932
2137:6715719
2116:Bibcode
2082:3207586
1943:7261191
1859:4914085
1810:7515708
1712:5828394
1663:4963239
1611:6065035
1516:5785279
1378:7554316
1327:7558717
648:(red).
382:introns
364:(red).
2634:
2599:
2558:
2517:
2507:
2463:
2455:
2409:
2399:
2350:
2340:
2296:
2286:
2245:
2237:
2198:
2188:
2144:
2134:
2080:
2072:
2037:
1991:
1950:
1940:
1901:
1866:
1856:
1817:
1807:
1768:
1761:140103
1758:
1719:
1709:
1670:
1660:
1618:
1608:
1564:
1523:
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