858:, scientists simulated the evolution of DNA sequences to analyze the emergence of features that underly enhancer function. This allowed the design and production of a range of functioning synthetic enhancers for different cell types of the fruit fly brain. A second approach trained artificial intelligence models on single-cell DNA accessibility data and transferred the learned models towards the prediction of enhancers for selected tissues in the fruit fly embryo. These enhancer prediction models were used to design synthetic enhancers for the nervous system, brain, muscle, epidermis and gut.
223:
305:), 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 factors (there are 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 level of transcription of the target gene.
29:
293:
enhancer DNA regions, for a particular type of tissue only specific enhancers are brought into proximity with the promoters that they regulate. In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to their target promoters. Multiple enhancers, each often at tens or hundreds of thousands of nucleotides distant from their target genes, loop to their target gene promoters and can coordinate with each other to control the expression of their common target gene.
685:
gene it regulates). On its own, each enhancer drives nearly identical patterns of gene expression. Are the two enhancers truly redundant? Recent work has shown that multiple enhancers allow fruit flies to survive environmental perturbations, such as an increase in temperature. When raised at an elevated temperature, a single enhancer sometimes fails to drive the complete pattern of expression, whereas the presence of both enhancers permits normal gene expression.
324:. An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor 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 transcription factor bound to enhancer in the illustration). An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene.
551:, yet both species' sequences produce nearly identical patterns of reporter gene expression in zebrafish. Similarly, in highly diverged insects (separated by around 350 million years), similar gene expression patterns of several key genes was found to be regulated through similarly constituted CRMs although these CRMs do not show any appreciable sequence conservation detectable by standard sequence alignment methods such as
22:
634:). The PEE turns on Nodal expression in response to a combination of Wnt signaling plus a second, unknown signal; thus, a member of the LEF/TCF transcription factor family likely binds to a TCF binding site in the cells in the node. Diffusion of Nodal away from the node forms a gradient which then patterns the extending anterior-posterior axis of the embryo. The ASE is an intronic enhancer bound by the
187:, which recruits polymerase II and the general transcription factors which then begin transcribing the genes. Enhancers can also be found within introns. An enhancer's orientation may even be reversed without affecting its function; additionally, an enhancer may be excised and inserted elsewhere in the chromosome, and still affect gene transcription. That is one reason that introns
105:. They can be located up to 1 Mbp (1,000,000 bp) away from the gene, upstream or downstream from the start site. There are hundreds of thousands of enhancers in the human genome. They are found in both prokaryotes and eukaryotes. Active enhancers typically get transcribed as enhancer or regulatory non-coding RNA, whose expression levels correlate with mRNA levels of target genes.
502:, clustering of known or predicted TF-binding sites, and supervised machine-learning approaches trained on known CRMs. All of these methods have proven effective for CRM discovery, but each has its own considerations and limitations, and each is subject to a greater or lesser number of false-positive identifications. In the
585:
transcription factors, thus creating zones within which different combinations of transcription factors are expressed. The pair-rule genes are separated from one another by non-expressing cells. Moreover, the stripes of expression for different pair-rule genes are offset by a few cell diameters from
684:
Some genes involved in critical developmental processes contain multiple enhancers of overlapping function. Secondary enhancers, or "shadow enhancers", may be found many kilobases away from the primary enhancer ("primary" usually refers to the first enhancer discovered, which is often closer to the
292:
Enhancers are regions 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. While there are hundreds of thousands of
822:
facilitates remodeling of chromatin in a manner that selectively redistributes cofactors from high-occupancy enhancers, thereby repressing genes involved in maintaining cellular identify whose expression they enhance; at the same time, this F-κB-driven remodeling and redistribution activates other
407:
An enhancer near the gene GADD45g has been described that may regulate brain growth in chimpanzees and other mammals, but not in humans. The GADD45G regulator in mice and chimps is active in regions of the brain where cells that form the cortex, ventral forebrain, and thalamus are located and may
258:
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
467:. If the reporter gene integrates near an enhancer, its expression will reflect the expression pattern driven by that enhancer. Thus, staining the flies for LacZ expression or activity and cloning the sequence surrounding the integration site allows the identification of the enhancer sequence.
671:
expression is controlled in the early embryo by an intronic enhancer that binds another forkhead domain transcription factor, FoxA2. Initially the enhancer drives broad gene expression throughout the embryo, but the expression quickly becomes restricted to the endoderm, suggesting that other
288:
have a leading role in the regulation of gene expression. An enhancer localized in a DNA region distant from the promoter of a gene can have a very large effect on gene expression, with some genes undergoing up to 100-fold increased expression due to an activated enhancer.
823:
enhancers that guide changes in cellular function through inflammation. As a result, inflammation reprograms cells, altering their interactions with the rest of tissue and with the immune system. In cancer, proteins that control NF-κB activity are dysregulated, permitting
275:
of genes. Core promoters are sufficient to direct transcription initiation, but generally have low basal activity. Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include enhancers,
781:
gene produce gene expression in precisely this pattern – the vein spot enhancer drives reporter gene expression in the 12 spots, and the intervein shade enhancer drives reporter expression in the 4 distinct patches. These two enhancers are responsive to the
586:
one another. Thus, unique combinations of pair-rule gene expression create spatial domains along the anterior-posterior axis to set up each of the 14 individual segments. The 480 bp enhancer responsible for driving the sharp stripe two of the pair-rule gene
116:, provided an explanation for the transcriptional activation of rearranged Vh gene promoters while unrearranged Vh promoters remained inactive. Lately, enhancers have been shown to be involved in certain medical conditions, for example,
543:. Although much evidence has pointed to sequence conservation for critical developmental enhancers, other work has shown that the function of enhancers can be conserved with little or no primary sequence conservation. For example, the
724:
gene involved in posterior limb development in vertebrates. Preliminary genetic analyses indicated that changes in the expression of this gene were responsible for pelvic reduction in sticklebacks. Fish expressing only the freshwater
309:(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 (pol II) enzyme bound to the promoter.
296:
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
839:
Synthetic regulatory elements such as enhancers promise to be a powerful tool to direct gene products to particular cell types in order to treat disease by activating beneficial genes or by halting aberrant cell states.
672:
repressors may be involved in its restriction. Late in development, the same enhancer restricts expression to the tissues that will become the stomach and pancreas. An additional enhancer is responsible for maintaining
164:, repress the transcription of the gene. Silencers and enhancers may be in close proximity to each other or may even be in the same region only differentiated by the transcription factor the region binds to.
249:
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
712:
fish. Sticklebacks exist in both marine and freshwater environments, but sticklebacks in many freshwater populations have completely lost their pelvic fins (appendages homologous to the posterior limb of
32:
Seen here is a four step diagram depicting the usage of an enhancer. Within this DNA sequence, protein(s) known as transcription factor(s) bind to the enhancer and increase the activity of the promoter.
514:
can be indicative of enhancers. Sequences from multiple species are aligned, and conserved regions are identified computationally. Identified sequences can then be attached to a reporter gene such as
733:
do not have pelvic spines, whereas fish expressing a marine allele retain pelvic spines. A more thorough characterization showed that a 500 base pair enhancer sequence is responsible for turning on
598:
is only expressed in a narrow stripe of cells that contain high concentrations of the activators and low concentration of the repressors for this enhancer sequence. Other enhancer regions drive
432:
and other DNA-binding proteins in a developing tissue controls which genes will be expressed in that tissue. Enhancers allow the same gene to be used in diverse processes in space and time.
814:". These enhancers contain a large number of binding sites for sequence-specific, inducible transcription factors, and regulate expression of genes involved in cell differentiation. During
1240:
Gillies SD, Morrison SL, Oi VT, Tonegawa S (July 1983). "A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene".
594:) has been well-characterized. The enhancer contains 12 different binding sites for maternal and gap gene transcription factors. Activating and repressing sites overlap in sequence.
657:
is another critical step in animal development. Each of the three germ layers has unique patterns of gene expression that promote their differentiation and development. The
408:
suppress further neurogenesis. Loss of the GADD45G enhancer in humans may contribute to an increase of certain neuronal populations and to forebrain expansion in humans.
254:
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
1194:
Banerji J, Olson L, Schaffner W (July 1983). "A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes".
697:("evo-devo") is investigating the role of enhancers and other cis-regulatory elements in producing morphological changes via developmental differences between species.
4096:
de
Almeida BP, Reiter F, Pagani M, Stark A (May 2022). "DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers".
1397:
de
Almeida BP, Reiter F, Pagani M, Stark A (May 2022). "DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers".
638:
transcription factor Fox1. Early in development, Fox1-driven Nodal expression establishes the visceral endoderm. Later in development, Fox1 binding to the ASE drives
183:
as first shown by in vivo competition experiments. Subsequently, molecular studies showed direct interactions with transcription factors and cofactors, including the
3426:
Norris DP, Brennan J, Bikoff EK, Robertson EJ (July 2002). "The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo".
478:(NGS) methods now enable high-throughput functional CRM discovery assays, and the vastly increasing amounts of available data, including large-scale libraries of
346:
Flexible billboards – less integrative, multiple proteins independently regulate gene expression and their sum is read in by the basal transcriptional machinery.
1701:
Scholer H, Haslinger A, Heguy A, Holtgreve H, Karin M (April 1986). "In vivo competition between a metallothionein regulatory element and the SV40 enhancer".
444:
techniques using a reporter gene or by comparative sequence analysis and computational genomics. In genetically tractable models such as the fruit fly
622:
gene contains two enhancers: the
Proximal Epiblast Enhancer (PEE) and the Asymmetric Enhancer (ASE). The PEE is upstream of the Nodal gene and drives
2904:
851:
strategies have led to a better understanding of the features of regulatory DNA sequences, the prediction, and the design of synthetic enhancers.
312:
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two
761:
Pigmentation patterns provide one of the most striking and easily scored differences between different species of animals. Pigmentation of the
1658:
Mercola M, Goverman J, Mirell C, Calame K (January 1985). "Immunoglobulin heavy-chain enhancer requires one or more tissue-specific factors".
749:
expression in the pelvic spines in isolated freshwater population, and without this enhancer, freshwater fish fail to develop pelvic spines.
618:
superfamily ligand, is a key gene involved in patterning both the anterior-posterior axis and the left-right axis of the early embryo. The
2001:
Spilianakis CG, Lalioti MD, Town T, Lee GR, Flavell RA (June 2005). "Interchromosomal associations between alternatively expressed loci".
810:
Each cell typically contains several hundred of a special class of enhancers that stretch over many kilobases long DNA sequences, called "
486:
data across many cell types, are making accurate computational CRM discovery an attainable goal. An example of NGS-based approach called
1151:
Mercola M, Wang XF, Olsen J, Calame K (August 1983). "Transcriptional enhancer elements in the mouse immunoglobulin heavy chain locus".
3471:"Direct transcriptional regulation of Gata4 during early endoderm specification is controlled by FoxA2 binding to an intronic enhancer"
490:
have enabled identification of nucleosome-depleted, or open chromatin regions, which can contain CRM. More recently techniques such as
494:
have been developed which require less starting material. Nucelosome depleted regions can be identified in vivo through expression of
3269:
3891:"Late-phase synthesis of IκBα insulates the TLR4-activated canonical NF-κB pathway from noncanonical NF-κB signaling in macrophages"
3632:
Werner T, Koshikawa S, Williams TM, Carroll SB (April 2010). "Generation of a novel wing colour pattern by the
Wingless morphogen".
3842:"Acute TNF-induced repression of cell identity genes is mediated by NFκB-directed redistribution of cofactors from super-enhancers"
4241:
4387:
160:
in the eukaryotic genome. Silencers are antagonists of enhancers that, when bound to its proper transcription factors called
3387:"Nodal cis-regulatory elements reveal epiblast and primitive endoderm heterogeneity in the peri-implantation mouse embryo"
854:
Building on work in cell culture, synthetic enhancers were successfully applied to entire living organisms in 2023. Using
765:
wing has proven to be a particularly amenable system for studying the development of complex pigmentation phenotypes. The
4619:
259:
interacting structure) communicates regulatory signals from the enhancer DNA-bound transcription factors to the promoter.
124:
to design synthetic enhancers and applied them in animal systems, first in a cell line, and one year later also in vivo.
694:
3338:"Asymmetric and node-specific nodal expression patterns are controlled by two distinct cis-acting regulatory elements"
769:
wing has 12 dark pigmentation spots and 4 lighter gray intervein patches. Pigment spots arise from expression of the
479:
4591:
4208:
2856:"Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems"
2709:"The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription"
615:
577:
transcription factors are responsible for activating and repressing a number of segmentation genes, such as the
4644:
2758:"A comparison of experimental assays and analytical methods for genome-wide identification of active enhancers"
179:
upstream or downstream of the start site. Enhancers do not act on the promoter region itself, but are bound by
4586:
3734:"Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants"
535:, which provides a more direct measure of enhancer activity, since it is not subjected to the complexities of
4639:
168:
4607:
4581:
3889:
Chatterjee B, Banoth B, Mukherjee T, Taye N, Vijayaragavan B, Chattopadhyay S, et al. (December 2016).
2466:
Schoenfelder S, Fraser P (August 2019). "Long-range enhancer-promoter contacts in gene expression control".
498:, allowing for greater control of cell-type specific enhancer identification. Computational methods include
741:—a sequence of DNA that is likely to be broken and thus more likely to be mutated as a result of imprecise
149:
3270:"Evidence for Deep Regulatory Similarities in Early Developmental Programs across Highly Diverged Insects"
470:
The development of genomic and epigenomic technologies, however, has dramatically changed the outlook for
4234:
3027:"Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements"
2943:
1092:
Burren OS, Rubio García A, Javierre BM, Rainbow DB, Cairns J, Cooper NJ, et al. (4 September 2017).
416:
The development, differentiation and growth of cells and tissues require precisely regulated patterns of
387:
on two legs". Evidence to date shows that of the 110,000 gene enhancer sequences identified in the human
207:
144:
DNA, so although the enhancer DNA may be far from the gene in a linear way, it is spatially close to the
3074:
Hartenstein V, Jan YN (June 1992). "Studying
Drosophila embryogenesis with P-lacZ enhancer trap lines".
4267:
4183:
3119:"CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo"
2807:"MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300"
2416:"Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression"
109:
2854:
Carullo NV, Phillips Iii RA, Simon RC, Soto SA, Hinds JE, Salisbury AJ, et al. (September 2020).
1495:
Taskiran II, Spanier KI, Dickmänken H, Kempynck N, Pančíková A, Ekşi EC, et al. (February 2024).
581:. The gap genes are expressed in blocks along the anterior-posterior axis of the fly along with other
4464:
4400:
4370:
4348:
2707:
Mikhaylichenko O, Bondarenko V, Harnett D, Schor IE, Males M, Viales RR, et al. (January 2018).
646:, thus establishing left-right asymmetry necessary for asymmetric organ development in the mesoderm.
610:
Establishing body axes is a critical step in animal development. During mouse embryonic development,
515:
365:
332:
As of 2005, there are two different theories on the information processing that occurs on enhancers:
745:. This fragile site has caused repeated, independent losses of the enhancer responsible for driving
4684:
4258:
4250:
4187:
3385:
Granier C, Gurchenkov V, Perea-Gomez A, Camus A, Ott S, Papanayotou C, et al. (January 2011).
738:
425:
272:
172:
140:
complex of DNA is folded in a way that functionally mimics the supercoiled state characteristic of
87:
3577:"Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer"
3289:"Dissecting the regulatory switches of development: lessons from enhancer evolution in Drosophila"
175:
initiation site to affect transcription, as some have been found located several hundred thousand
4565:
4254:
844:
790:
expression at all of the pigmented locations. Thus, in the evolution of the complex pigmentation
569:
446:
246:
121:
117:
3685:"Master transcription factors and mediator establish super-enhancers at key cell identity genes"
887:
Blackwood EM, Kadonaga JT (July 1998). "Going the distance: a current view of enhancer action".
4474:
4227:
3732:
Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, et al. (October 2013).
2054:"Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes"
1348:
Zhigulev A, Norberg Z, Cordier J, Spalinskas R, Bassereh H, Björn N, et al. (March 2024).
573:
embryos are among the best characterized developmental enhancers. In the early fly embryo, the
564:
421:
306:
264:
188:
184:
99:
2968:
McLean CY, Reno PL, Pollen AA, Bassan AI, Capellini TD, Guenther C, et al. (March 2011).
4658:
4653:
4521:
4423:
4131:
Avsec Ž, Weilert M, Shrikumar A, Krueger S, Alexandari A, Dalal K, et al. (March 2021).
3995:
Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, et al. (August 2015).
3575:
Chan YF, Marks ME, Jones FC, Villarreal G, Shapiro MD, Brady SD, et al. (January 2010).
2509:
Weintraub AS, Li CH, Zamudio AV, Sigova AA, Hannett NM, Day DS, et al. (December 2017).
783:
552:
536:
532:
528:
471:
429:
285:
284:
and tethering elements. Among this constellation of elements, enhancers and their associated
192:
2103:"Histone modifications at human enhancers reflect global cell-type-specific gene expression"
1854:"Exonic remnants of whole-genome duplication reveal cis-regulatory function of coding exons"
1803:
Ramasamy S, Aljahani A, Karpinska MA, Cao TB, Velychko T, Cruz JN, et al. (July 2023).
368:
2) is a gene enhancer "that may have contributed to the evolution of the uniquely opposable
4555:
4469:
4435:
4329:
3997:"Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment"
3951:
3791:
Brown JD, Lin CY, Duan Q, Griffin G, Federation A, Paranal RM, et al. (October 2014).
3745:
3641:
3588:
3531:
2981:
2612:
2368:(September 2012). "Transcription factors: from enhancer binding to developmental control".
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2114:
2010:
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1710:
1667:
1614:
1508:
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in specific cells and/or repressing it in other cells. Thus, the particular combination of
281:
251:
180:
95:
83:
4046:"Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA"
3273:
2101:
Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, et al. (May 2009).
1601:
Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, et al. (March 2014).
1570:
1553:
1012:
995:
708:
Recent work has investigated the role of enhancers in morphological changes in threespine
8:
4506:
4392:
4366:
2414:
Beagan JA, Pastuzyn ED, Fernandez LR, Guo MH, Feng K, Titus KR, et al. (June 2020).
1603:"Obesity-associated variants within FTO form long-range functional connections with IRX3"
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230:
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3535:
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Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. (February 2018).
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2014:
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1529:
1512:
1496:
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of the gene it regulates. Furthermore, an enhancer does not need to be located near the
4307:
4157:
4132:
4070:
4045:
4021:
3996:
3972:
3939:
3938:
Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, et al. (April 2015).
3915:
3890:
3866:
3841:
3817:
3792:
3768:
3733:
3709:
3684:
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Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. (April 2013).
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3609:
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3313:
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2440:
2415:
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2314:
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Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, et al. (September 2010).
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2034:
1978:
1951:
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1902:
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Birnbaum RY, Clowney EJ, Agamy O, Kim MJ, Zhao J, Yamanaka T, et al. (June 2012).
1878:
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145:
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3337:
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1780:
1745:
1437:"Targeted design of synthetic enhancers for selected tissues in the Drosophila embryo"
1094:"Chromosome contacts in activated T cells identify autoimmune disease candidate genes"
4626:
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4113:
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4026:
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3714:
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3614:
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1983:
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242:
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to decrease their dependence on interactions with local tissue, and hindering their
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2867:
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2728:
2720:
2679:
2671:
2630:
2620:
2601:"Positional specificity of different transcription factor classes within enhancers"
2571:
2530:
2522:
2475:
2435:
2427:
2377:
2336:
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2285:
2277:
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2228:
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Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, et al. (September 2009).
2038:
2018:
1973:
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1435:
de
Almeida BP, Schaub C, Pagani M, Secchia S, Furlong EE, Stark A (February 2024).
1406:
1369:
1361:
1350:"Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression"
1320:
1310:
1249:
1203:
1168:
1123:
1105:
1064:
1056:
1043:
Kulaeva OI, Nizovtseva EV, Polikanov YS, Ulianov SV, Studitsky VM (December 2012).
1007:
966:
958:
904:
635:
627:
16:
DNA sequence that binds activators to increase the likelihood of gene transcription
4012:
3793:"NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis"
2970:"Human-specific loss of regulatory DNA and the evolution of human-specific traits"
2805:
Li QJ, Yang SH, Maeda Y, Sladek FM, Sharrocks AD, Martins-Green M (January 2003).
2158:
Visel A, Blow MJ, Li Z, Zhang T, Akiyama JA, Holt A, et al. (February 2009).
1315:
522:
pattern of gene expression produced by the enhancer when injected into an embryo.
4412:
4133:"Base-resolution models of transcription-factor binding reveal soft motif syntax"
3840:
Schmidt SF, Larsen BD, Loft A, Nielsen R, Madsen JG, Mandrup S (September 2015).
3808:
3237:
1968:
1852:
Dong X, Navratilova P, Fredman D, Drivenes Ø, Becker TS, Lenhard B (March 2010).
867:
582:
578:
540:
417:
340:
255:
211:
3486:
3403:
3386:
2266:"Eukaryotic core promoters and the functional basis of transcription initiation"
908:
4622:
4610:
4560:
4193:
4148:
4109:
3738:
Proceedings of the
National Academy of Sciences of the United States of America
3700:
2773:
2605:
Proceedings of the
National Academy of Sciences of the United States of America
2576:
2559:
2526:
2365:
2069:
1820:
1750:
Proceedings of the
National Academy of Sciences of the United States of America
1520:
1460:
1410:
824:
811:
631:
475:
339:– rely on highly cooperative, coordinated action and can be disabled by single
321:
229:. An active enhancer regulatory region of DNA is enabled to interact with the
157:
28:
3906:
3543:
3042:
2905:"Transcriptional enhancers: Intelligent enhanceosomes or flexible billboards?"
2599:
Grossman SR, Engreitz J, Ray JP, Nguyen TH, Hacohen N, Lander ES (July 2018).
2479:
2431:
2331:
2281:
1305:
1110:
676:
expression in the endoderm during the intermediate stages of gut development.
4678:
4324:
1119:
855:
523:
511:
441:
317:
238:
3758:
3600:
3439:
2625:
1770:
1722:
1679:
1172:
4166:
4117:
4079:
4030:
3981:
3924:
3875:
3826:
3777:
3718:
3661:
3618:
3561:
3504:
3447:
3412:
3371:
3353:
3322:
3255:
3203:
3154:
3117:
Aughey GN, Estacio Gomez A, Thomson J, Yin H, Southall TD (February 2018).
3095:
3060:
3011:
2931:
2889:
2840:
2822:
2791:
2742:
2724:
2693:
2644:
2585:
2544:
2487:
2449:
2389:
2350:
2299:
2250:
2201:
2144:
2087:
2030:
1987:
1936:
1887:
1838:
1789:
1644:
1579:
1538:
1478:
1418:
1383:
1365:
1334:
1137:
1078:
1021:
980:
815:
654:
336:
313:
3940:"Super-enhancers delineate disease-associated regulatory nodes in T cells"
3857:
2871:
1918:
1869:
1730:
1687:
1261:
1215:
1180:
916:
424:
to mediate both spatial and temporal control of development by turning on
4511:
4479:
4382:
4061:
1060:
709:
650:
396:
141:
4044:
Zou Z, Huang B, Wu X, Zhang H, Qi J, Bradner J, et al. (May 2014).
3963:
3653:
3135:
2993:
2315:"The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1"
2183:
2126:
2022:
1626:
945:
Pennacchio LA, Bickmore W, Dean A, Nobrega MA, Bejerano G (April 2013).
4663:
4357:
4312:
4302:
4297:
4292:
4287:
3304:
3087:
742:
547:
enhancers in humans have very little sequence conservation to those in
483:
200:
176:
133:
4091:
4089:
3170:"Identifying transcriptional cis-regulatory modules in animal genomes"
2923:
679:
4319:
3185:
1235:
1233:
798:
pigment gene evolved enhancers responsive to the wingless signal and
791:
737:
expression in the posterior fin bud. This enhancer is located near a
548:
487:
461:
392:
161:
137:
71:
2706:
2675:
2381:
2160:"ChIP-seq accurately predicts tissue-specific activity of enhancers"
1903:"Coding exons function as tissue-specific enhancers of nearby genes"
1746:"Association of the Mediator complex with enhancers of active genes"
1045:"Distant activation of transcription: mechanisms of enhancer action"
962:
802:
expression evolved at new locations to produce novel wing patterns.
4526:
4516:
4086:
2312:
2232:
1283:
Hauptman G, Reichert MC, Abdal Rhida MA, Evans TA (December 2022).
721:
658:
643:
574:
491:
63:
3469:
Rojas A, Schachterle W, Xu SM, Martín F, Black BL (October 2010).
1230:
819:
4486:
4353:
3384:
1494:
1091:
1042:
774:
667:
expression, and Gata4 goes on to direct gut morphogenesis later.
199:
region of an unrelated gene and they may act on genes on another
79:
1347:
1282:
21:
4282:
3520:"Shadow enhancers foster robustness of Drosophila gastrulation"
1805:"The Mediator complex regulates enhancer-promoter interactions"
726:
630:
that will differentiate into the node (also referred to as the
388:
361:
113:
4203:
3631:
3518:
Perry MW, Boettiger AN, Bothma JP, Levine M (September 2010).
1851:
1700:
4543:
4395:
4198:
3888:
3116:
2660:"The Mediator complex: a central integrator of transcription"
2217:"ChIP-Seq identification of weakly conserved heart enhancers"
2100:
1434:
944:
716:
663:
611:
495:
376:
372:
369:
343:
that move or remove the binding sites of individual proteins.
4130:
3425:
2853:
2756:
Yao L, Liang J, Ozer A, Leung AK, Lis JT, Yu H (July 2022).
2313:
Verheul TC, van Hijfte L, Perenthaler E, Barakat TS (2020).
1802:
4614:
4444:
4375:
4095:
1657:
1396:
834:
457:
453:
384:
380:
298:
234:
196:
91:
3517:
2511:"YY1 Is a Structural Regulator of Enhancer-Promoter Loops"
2413:
482:, collections of annotated, validated CRMs, and extensive
237:
by the formation of a chromosome loop. This can initiate
4249:
3731:
2598:
2557:
2000:
1554:"Transcriptional regulatory elements in the human genome"
1239:
996:"Transcriptional regulatory elements in the human genome"
302:
75:
3994:
3937:
3839:
3682:
3574:
3468:
2508:
688:
108:
The first discovery of a eukaryotic enhancer was in the
1900:
752:
3222:"Enhancer identification through comparative genomics"
3219:
3174:
2967:
1743:
1150:
435:
94:
will occur. These proteins are usually referred to as
3287:
Borok MJ, Tran DA, Ho MC, Drewell RA (January 2010).
3024:
1193:
395:
of humans following the split with the ancestors of
3790:
3220:Visel A, Bristow J, Pennacchio LA (February 2007).
3025:Barrett LW, Fletcher S, Wilton SD (November 2012).
2214:
1949:
1894:
1744:Kuras L, Borggrefe T, Kornberg RD (November 2003).
1600:
680:
Multiple enhancers promote developmental robustness
460:can be randomly integrated into the genome using a
3286:
2465:
2051:
1497:"Cell-type-directed design of synthetic enhancers"
777:. Recent work has shown that two enhancers in the
391:, HACNS1 has undergone the most change during the
112:gene in 1983. This enhancer, located in the large
2804:
2755:
886:
642:expression on the left side of the lateral plate
4676:
3167:
2157:
1552:Maston GA, Evans SK, Green MR (1 January 2006).
1551:
993:
526:expression of the reporter can be visualized by
263:Gene expression in mammals is regulated by many
4043:
3335:
2902:
2461:
2459:
1490:
1488:
1430:
1428:
480:transcription factor-binding site (TFBS) motifs
350:
3272:. Genome Biology and Evolution. Archived from
3073:
451:for example, a reporter construct such as the
148:and gene. This allows it to interact with the
4235:
1952:"De novo genesis of enhancers in vertebrates"
805:
602:expression in 6 other stripes in the embryo.
558:
320:, these eRNAs are usually protected by their
269:core promoters and promoter-proximal elements
3226:Seminars in Cell & Developmental Biology
3215:
3213:
2847:
2798:
2700:
2657:
2651:
2592:
2551:
2502:
2456:
2363:
2357:
2306:
2263:
2257:
1950:Eichenlaub MP, Ettwiller L (November 2011).
1558:Annual Review of Genomics and Human Genetics
1485:
1425:
1390:
1000:Annual Review of Genomics and Human Genetics
940:
938:
936:
934:
440:Traditionally, enhancers were identified by
2319:Frontiers in Cell and Developmental Biology
1694:
1285:"Characterization of enhancer fragments in
605:
411:
316:(eRNAs) as illustrated in the Figure. Like
4242:
4228:
4211:Enhancer discovery and characterization.
217:
4186:at the U.S. National Library of Medicine
4156:
4069:
4020:
3971:
3914:
3865:
3816:
3767:
3757:
3708:
3608:
3551:
3494:
3402:
3361:
3312:
3245:
3210:
3193:
3144:
3134:
3050:
3001:
2879:
2830:
2781:
2732:
2683:
2634:
2624:
2575:
2534:
2439:
2409:
2407:
2340:
2330:
2289:
2240:
2191:
2134:
2077:
1977:
1967:
1926:
1877:
1828:
1809:Nature Structural & Molecular Biology
1779:
1769:
1634:
1569:
1528:
1468:
1373:
1324:
1314:
1304:
1127:
1109:
1068:
1011:
970:
931:
375:, and possibly also modifications in the
3076:Roux's Archives of Developmental Biology
835:Designing enhancers in synthetic biology
221:
27:
20:
245:(RNAP II) bound to the promoter at the
210:and their location can be predicted by
191:may have effects although they are not
4677:
2903:Arnosti DN, Kulkarni MM (April 2005).
2664:Nature Reviews. Molecular Cell Biology
2404:
2270:Nature Reviews. Molecular Cell Biology
994:Maston GA, Evans SK, Green MR (2006).
227:Regulation of transcription in mammals
4388:Histone acetylation and deacetylation
4223:
3336:Norris DP, Robertson EJ (June 1999).
1571:10.1146/annurev.genom.7.080505.115623
1013:10.1146/annurev.genom.7.080505.115623
947:"Enhancers: five essential questions"
689:Evolution of developmental mechanisms
661:is specified early in development by
214:against this family of coactivators.
195:. Enhancers can also be found at the
4001:Cytokine & Growth Factor Reviews
3031:Cellular and Molecular Life Sciences
1994:
700:
156:. The same mechanism holds true for
2896:
2658:Allen BL, Taatjes DJ (March 2015).
2264:Haberle V, Stark A (October 2018).
773:gene, whose product produces black
436:Identification and characterization
120:. Since 2022, scientists have used
13:
695:evolutionary developmental biology
86:) to increase the likelihood that
14:
4696:
4177:
2560:"The Human Transcription Factors"
829:surveillance by the immune system
626:expression in the portion of the
3168:Suryamohan K, Halfon MS (2014).
2912:Journal of Cellular Biochemistry
563:The enhancers determining early
4592:Archaeal transcription factor B
4124:
4037:
3988:
3931:
3882:
3833:
3784:
3725:
3676:
3625:
3568:
3511:
3462:
3419:
3378:
3329:
3280:
3262:
3161:
3110:
3067:
3018:
2961:
2749:
2208:
2151:
2094:
2045:
1943:
1845:
1796:
1737:
1651:
1594:
1545:
1341:
616:transforming growth factor-beta
49:Transcription Activator Protein
1276:
1187:
1144:
1085:
1049:Molecular and Cellular Biology
1036:
987:
880:
1:
4013:10.1016/j.cytogfr.2015.06.001
1316:10.1080/19336934.2022.2126259
873:
150:general transcription factors
3809:10.1016/j.molcel.2014.08.024
3238:10.1016/j.semcdb.2006.12.014
1969:10.1371/journal.pbio.1001188
1254:10.1016/0092-8674(83)90014-4
1208:10.1016/0092-8674(83)90015-6
351:Examples in the human genome
127:
7:
3487:10.1016/j.ydbio.2010.07.032
3404:10.1016/j.ydbio.2010.10.036
909:10.1126/science.281.5373.60
861:
818:, the transcription factor
327:
167:An enhancer may be located
136:cells the structure of the
10:
4701:
4268:Transcriptional regulation
4149:10.1038/s41588-021-00782-6
4110:10.1038/s41588-022-01048-5
3701:10.1016/j.cell.2013.03.035
2774:10.1038/s41587-022-01211-7
2577:10.1016/j.cell.2018.01.029
2527:10.1016/j.cell.2017.11.008
2070:10.1016/j.cell.2009.06.049
1821:10.1038/s41594-023-01027-2
1521:10.1038/s41586-023-06936-2
1461:10.1038/s41586-023-06905-9
1411:10.1038/s41588-022-01048-5
806:In inflammation and cancer
559:In segmentation of insects
476:Next-generation sequencing
402:
271:that are located near the
110:immunoglobulin heavy chain
4635:
4600:
4574:
4499:
4465:Transcription coregulator
4457:
4434:
4411:
4401:Histone acetyltransferase
4371:Histone methyltransferase
4349:Histone-modifying enzymes
4347:
4340:
4275:
4266:
4184:Enhancer+Elements,Genetic
3907:10.1126/scisignal.aaf1129
3544:10.1016/j.cub.2010.07.043
3043:10.1007/s00018-012-0990-9
2480:10.1038/s41576-019-0128-0
2432:10.1038/s41593-020-0634-6
2332:10.3389/fcell.2020.592164
2282:10.1038/s41580-018-0028-8
1306:10.1101/2022.08.01.502399
1111:10.1186/s13059-017-1285-0
693:One theme of research in
518:or lacZ to determine the
516:green fluorescent protein
355:
273:transcription start sites
233:DNA region of its target
4188:Medical Subject Headings
2468:Nature Reviews. Genetics
2370:Nature Reviews. Genetics
951:Nature Reviews. Genetics
786:, which is activated by
739:chromosomal fragile site
606:In vertebrate patterning
412:In developmental biology
366:Human Accelerated Region
247:transcription start site
4566:Internal control region
4209:ENCODE threads explorer
3759:10.1073/pnas.1317023110
3601:10.1126/science.1182213
3440:10.1242/dev.129.14.3455
3342:Genes & Development
2713:Genes & Development
2626:10.1073/pnas.1804663115
1771:10.1073/pnas.2036346100
1723:10.1126/science.3006253
1680:10.1126/science.3917575
1173:10.1126/science.6306772
845:artificial intelligence
570:Drosophila melanogaster
447:Drosophila melanogaster
422:cis-regulatory elements
265:cis-regulatory elements
218:Role in gene expression
206:Enhancers are bound by
122:artificial intelligence
3354:10.1101/gad.13.12.1575
2860:Nucleic Acids Research
2725:10.1101/gad.308619.117
1858:Nucleic Acids Research
1366:10.26508/lsa.202302244
757:wing pattern evolution
472:cis-regulatory modules
360:HACNS1 (also known as
260:
169:upstream or downstream
59:
25:
4659:Intrinsic termination
4424:DNA methyltransferase
3858:10.1101/gr.188300.114
3475:Developmental Biology
3391:Developmental Biology
1919:10.1101/gr.133546.111
1354:Life Science Alliance
784:Wnt signaling pathway
508:sequence conservation
430:transcription factors
383:that allow humans to
286:transcription factors
252:transcription factors
225:
96:transcription factors
78:that can be bound by
31:
24:
4436:Chromatin remodeling
4062:10.1038/onc.2013.179
2823:10.1093/emboj/cdg028
2762:Nature Biotechnology
2521:(7): 1573–1588.e28.
1061:10.1128/MCB.01127-12
856:deep neural networks
767:Drosophila guttifera
504:comparative genomics
500:comparative genomics
420:. Enhancers work as
241:(mRNA) synthesis by
70:is a short (50–1500
4393:Histone deacetylase
4383:Histone demethylase
4367:Histone methylation
3964:10.1038/nature14154
3956:2015Natur.520..558V
3750:2013PNAS..11017921P
3744:(44): 17921–17926.
3654:10.1038/nature08896
3646:2010Natur.464.1143W
3640:(7292): 1143–1148.
3593:2010Sci...327..302C
3536:2010CBio...20.1562P
3136:10.7554/eLife.32341
2994:10.1038/nature09774
2986:2011Natur.471..216M
2872:10.1093/nar/gkaa671
2617:2018PNAS..115E7222G
2611:(30): E7222–E7230.
2420:Nature Neuroscience
2184:10.1038/nature07730
2176:2009Natur.457..854V
2127:10.1038/nature07829
2119:2009Natur.459..108H
2023:10.1038/nature03574
2015:2005Natur.435..637S
1870:10.1093/nar/gkp1124
1762:2003PNAS..10013887K
1756:(24): 13887–13891.
1715:1986Sci...232...76S
1672:1985Sci...227..266M
1627:10.1038/nature13138
1619:2014Natur.507..371S
1513:2024Natur.626..212T
1453:2024Natur.626..207D
1165:1983Sci...221..663M
901:1998Sci...281...60.
649:Establishing three
364:and located in the
3305:10.1242/dev.036160
3088:10.1007/BF00188752
512:non-coding regions
261:
181:activator proteins
60:
26:
4672:
4671:
4627:RNA polymerase II
4495:
4494:
4453:
4452:
4056:(18): 2395–2404.
3950:(7548): 558–562.
3895:Science Signaling
3587:(5963): 302–305.
3530:(17): 1562–1567.
3434:(14): 3455–3468.
3348:(12): 1575–1588.
3037:(21): 3613–3634.
2980:(7337): 216–219.
2924:10.1002/jcb.20352
2866:(17): 9550–9570.
2170:(7231): 854–858.
2113:(7243): 108–112.
2009:(7042): 637–645.
1666:(4684): 266–270.
1613:(7492): 371–375.
1507:(7997): 212–220.
1447:(7997): 207–211.
1360:(3): e202302244.
1159:(4611): 663–665.
1055:(24): 4892–4897.
849:transfer learning
474:(CRM) discovery.
243:RNA polymerase II
154:RNA polymerase II
4692:
4549:Response element
4532:Response element
4345:
4344:
4273:
4272:
4244:
4237:
4230:
4221:
4220:
4171:
4170:
4160:
4128:
4122:
4121:
4093:
4084:
4083:
4073:
4041:
4035:
4034:
4024:
3992:
3986:
3985:
3975:
3935:
3929:
3928:
3918:
3886:
3880:
3879:
3869:
3852:(9): 1281–1294.
3837:
3831:
3830:
3820:
3788:
3782:
3781:
3771:
3761:
3729:
3723:
3722:
3712:
3680:
3674:
3673:
3629:
3623:
3622:
3612:
3572:
3566:
3565:
3555:
3515:
3509:
3508:
3498:
3466:
3460:
3459:
3423:
3417:
3416:
3406:
3382:
3376:
3375:
3365:
3333:
3327:
3326:
3316:
3284:
3278:
3277:
3276:on 10 July 2015.
3266:
3260:
3259:
3249:
3217:
3208:
3207:
3197:
3186:10.1002/wdev.168
3165:
3159:
3158:
3148:
3138:
3114:
3108:
3107:
3071:
3065:
3064:
3054:
3022:
3016:
3015:
3005:
2965:
2959:
2958:
2956:
2954:
2948:
2942:. Archived from
2909:
2900:
2894:
2893:
2883:
2851:
2845:
2844:
2834:
2811:The EMBO Journal
2802:
2796:
2795:
2785:
2768:(7): 1056–1065.
2753:
2747:
2746:
2736:
2704:
2698:
2697:
2687:
2655:
2649:
2648:
2638:
2628:
2596:
2590:
2589:
2579:
2555:
2549:
2548:
2538:
2506:
2500:
2499:
2463:
2454:
2453:
2443:
2411:
2402:
2401:
2361:
2355:
2354:
2344:
2334:
2310:
2304:
2303:
2293:
2261:
2255:
2254:
2244:
2212:
2206:
2205:
2195:
2155:
2149:
2148:
2138:
2098:
2092:
2091:
2081:
2064:(5): 1019–1031.
2049:
2043:
2042:
1998:
1992:
1991:
1981:
1971:
1962:(11): e1001188.
1947:
1941:
1940:
1930:
1913:(6): 1059–1068.
1898:
1892:
1891:
1881:
1864:(4): 1071–1085.
1849:
1843:
1842:
1832:
1800:
1794:
1793:
1783:
1773:
1741:
1735:
1734:
1698:
1692:
1691:
1655:
1649:
1648:
1638:
1598:
1592:
1591:
1573:
1549:
1543:
1542:
1532:
1492:
1483:
1482:
1472:
1432:
1423:
1422:
1394:
1388:
1387:
1377:
1345:
1339:
1338:
1328:
1318:
1308:
1287:Drosophila robo2
1280:
1274:
1273:
1237:
1228:
1227:
1191:
1185:
1184:
1148:
1142:
1141:
1131:
1113:
1089:
1083:
1082:
1072:
1040:
1034:
1033:
1015:
991:
985:
984:
974:
942:
929:
928:
884:
868:Shadow enhancers
636:fork head domain
628:primitive streak
185:mediator complex
118:myelosuppression
98:. Enhancers are
90:of a particular
52:Mediator Protein
4700:
4699:
4695:
4694:
4693:
4691:
4690:
4689:
4685:Gene expression
4675:
4674:
4673:
4668:
4643:
4637:
4631:
4596:
4570:
4491:
4449:
4430:
4413:DNA methylation
4407:
4351:
4336:
4262:
4248:
4180:
4175:
4174:
4137:Nature Genetics
4129:
4125:
4098:Nature Genetics
4094:
4087:
4042:
4038:
3993:
3989:
3936:
3932:
3887:
3883:
3846:Genome Research
3838:
3834:
3789:
3785:
3730:
3726:
3681:
3677:
3630:
3626:
3573:
3569:
3524:Current Biology
3516:
3512:
3467:
3463:
3424:
3420:
3383:
3379:
3334:
3330:
3285:
3281:
3268:
3267:
3263:
3218:
3211:
3166:
3162:
3115:
3111:
3072:
3068:
3023:
3019:
2966:
2962:
2952:
2950:
2949:on 21 July 2006
2946:
2907:
2901:
2897:
2852:
2848:
2803:
2799:
2754:
2750:
2705:
2701:
2676:10.1038/nrm3951
2656:
2652:
2597:
2593:
2556:
2552:
2507:
2503:
2464:
2457:
2412:
2405:
2382:10.1038/nrg3207
2362:
2358:
2311:
2307:
2276:(10): 621–637.
2262:
2258:
2221:Nature Genetics
2213:
2209:
2156:
2152:
2099:
2095:
2050:
2046:
1999:
1995:
1948:
1944:
1907:Genome Research
1899:
1895:
1850:
1846:
1815:(7): 991–1000.
1801:
1797:
1742:
1738:
1709:(4746): 76–80.
1699:
1695:
1656:
1652:
1599:
1595:
1550:
1546:
1493:
1486:
1433:
1426:
1399:Nature Genetics
1395:
1391:
1346:
1342:
1281:
1277:
1238:
1231:
1192:
1188:
1149:
1145:
1090:
1086:
1041:
1037:
992:
988:
963:10.1038/nrg3458
943:
932:
895:(5373): 60–63.
885:
881:
876:
864:
837:
825:malignant cells
812:super-enhancers
808:
759:
714:
706:
691:
682:
608:
583:maternal effect
579:pair rule genes
561:
541:protein folding
438:
418:gene expression
414:
405:
358:
353:
341:point mutations
330:
256:phosphorylation
220:
130:
58:
17:
12:
11:
5:
4698:
4688:
4687:
4670:
4669:
4667:
4666:
4661:
4656:
4650:
4648:
4633:
4632:
4630:
4629:
4623:RNA polymerase
4617:
4611:RNA polymerase
4604:
4602:
4598:
4597:
4595:
4594:
4589:
4584:
4578:
4576:
4572:
4571:
4569:
4568:
4563:
4558:
4553:
4552:
4551:
4546:
4536:
4535:
4534:
4529:
4524:
4519:
4514:
4503:
4501:
4497:
4496:
4493:
4492:
4490:
4489:
4484:
4483:
4482:
4477:
4472:
4461:
4459:
4455:
4454:
4451:
4450:
4448:
4447:
4441:
4439:
4432:
4431:
4429:
4428:
4427:
4426:
4418:
4416:
4409:
4408:
4406:
4405:
4404:
4403:
4398:
4385:
4380:
4379:
4378:
4363:
4361:
4342:
4338:
4337:
4335:
4334:
4333:
4332:
4327:
4317:
4316:
4315:
4310:
4305:
4300:
4295:
4290:
4279:
4277:
4270:
4264:
4263:
4247:
4246:
4239:
4232:
4224:
4218:
4217:
4206:
4201:
4196:
4191:
4179:
4178:External links
4176:
4173:
4172:
4143:(3): 354–366.
4123:
4104:(5): 613–624.
4085:
4036:
4007:(4): 389–403.
3987:
3930:
3901:(457): ra120.
3881:
3832:
3803:(2): 219–231.
3797:Molecular Cell
3783:
3724:
3695:(2): 307–319.
3675:
3624:
3567:
3510:
3481:(2): 346–355.
3461:
3418:
3397:(2): 350–362.
3377:
3328:
3279:
3261:
3232:(1): 140–152.
3209:
3160:
3109:
3082:(4): 194–220.
3066:
3017:
2960:
2918:(5): 890–898.
2895:
2846:
2817:(2): 281–291.
2797:
2748:
2699:
2670:(3): 155–166.
2650:
2591:
2570:(4): 650–665.
2550:
2501:
2474:(8): 437–455.
2455:
2426:(6): 707–717.
2403:
2376:(9): 613–626.
2356:
2305:
2256:
2233:10.1038/ng.650
2227:(9): 806–810.
2207:
2150:
2093:
2044:
1993:
1942:
1893:
1844:
1795:
1736:
1693:
1650:
1593:
1544:
1484:
1424:
1405:(5): 613–624.
1389:
1340:
1299:(1): 312–346.
1275:
1248:(3): 717–728.
1229:
1202:(3): 729–740.
1186:
1143:
1098:Genome Biology
1084:
1035:
986:
957:(4): 288–295.
930:
878:
877:
875:
872:
871:
870:
863:
860:
836:
833:
807:
804:
758:
751:
705:
699:
690:
687:
681:
678:
632:primitive node
607:
604:
560:
557:
437:
434:
413:
410:
404:
401:
357:
354:
352:
349:
348:
347:
344:
329:
326:
219:
216:
129:
126:
57:
56:
55:RNA Polymerase
53:
50:
47:
44:
41:
38:
34:
15:
9:
6:
4:
3:
2:
4697:
4686:
4683:
4682:
4680:
4665:
4662:
4660:
4657:
4655:
4652:
4651:
4649:
4646:
4641:
4634:
4628:
4624:
4621:
4618:
4616:
4612:
4609:
4606:
4605:
4603:
4599:
4593:
4590:
4588:
4585:
4583:
4580:
4579:
4577:
4573:
4567:
4564:
4562:
4559:
4557:
4554:
4550:
4547:
4545:
4542:
4541:
4540:
4537:
4533:
4530:
4528:
4525:
4523:
4520:
4518:
4515:
4513:
4510:
4509:
4508:
4505:
4504:
4502:
4498:
4488:
4485:
4481:
4478:
4476:
4473:
4471:
4468:
4467:
4466:
4463:
4462:
4460:
4456:
4446:
4443:
4442:
4440:
4437:
4433:
4425:
4422:
4421:
4420:
4419:
4417:
4414:
4410:
4402:
4399:
4397:
4394:
4391:
4390:
4389:
4386:
4384:
4381:
4377:
4374:
4373:
4372:
4368:
4365:
4364:
4362:
4359:
4355:
4350:
4346:
4343:
4339:
4331:
4330:trp repressor
4328:
4326:
4325:lac repressor
4323:
4322:
4321:
4318:
4314:
4311:
4309:
4306:
4304:
4301:
4299:
4296:
4294:
4291:
4289:
4286:
4285:
4284:
4281:
4280:
4278:
4274:
4271:
4269:
4265:
4260:
4256:
4252:
4251:Transcription
4245:
4240:
4238:
4233:
4231:
4226:
4225:
4222:
4216:
4215:
4210:
4207:
4205:
4202:
4200:
4197:
4195:
4192:
4189:
4185:
4182:
4181:
4168:
4164:
4159:
4154:
4150:
4146:
4142:
4138:
4134:
4127:
4119:
4115:
4111:
4107:
4103:
4099:
4092:
4090:
4081:
4077:
4072:
4067:
4063:
4059:
4055:
4051:
4047:
4040:
4032:
4028:
4023:
4018:
4014:
4010:
4006:
4002:
3998:
3991:
3983:
3979:
3974:
3969:
3965:
3961:
3957:
3953:
3949:
3945:
3941:
3934:
3926:
3922:
3917:
3912:
3908:
3904:
3900:
3896:
3892:
3885:
3877:
3873:
3868:
3863:
3859:
3855:
3851:
3847:
3843:
3836:
3828:
3824:
3819:
3814:
3810:
3806:
3802:
3798:
3794:
3787:
3779:
3775:
3770:
3765:
3760:
3755:
3751:
3747:
3743:
3739:
3735:
3728:
3720:
3716:
3711:
3706:
3702:
3698:
3694:
3690:
3686:
3679:
3671:
3667:
3663:
3659:
3655:
3651:
3647:
3643:
3639:
3635:
3628:
3620:
3616:
3611:
3606:
3602:
3598:
3594:
3590:
3586:
3582:
3578:
3571:
3563:
3559:
3554:
3549:
3545:
3541:
3537:
3533:
3529:
3525:
3521:
3514:
3506:
3502:
3497:
3492:
3488:
3484:
3480:
3476:
3472:
3465:
3457:
3453:
3449:
3445:
3441:
3437:
3433:
3429:
3422:
3414:
3410:
3405:
3400:
3396:
3392:
3388:
3381:
3373:
3369:
3364:
3359:
3355:
3351:
3347:
3343:
3339:
3332:
3324:
3320:
3315:
3310:
3306:
3302:
3298:
3294:
3290:
3283:
3275:
3271:
3265:
3257:
3253:
3248:
3243:
3239:
3235:
3231:
3227:
3223:
3216:
3214:
3205:
3201:
3196:
3191:
3187:
3183:
3179:
3175:
3171:
3164:
3156:
3152:
3147:
3142:
3137:
3132:
3128:
3124:
3120:
3113:
3105:
3101:
3097:
3093:
3089:
3085:
3081:
3077:
3070:
3062:
3058:
3053:
3048:
3044:
3040:
3036:
3032:
3028:
3021:
3013:
3009:
3004:
2999:
2995:
2991:
2987:
2983:
2979:
2975:
2971:
2964:
2945:
2941:
2937:
2933:
2929:
2925:
2921:
2917:
2913:
2906:
2899:
2891:
2887:
2882:
2877:
2873:
2869:
2865:
2861:
2857:
2850:
2842:
2838:
2833:
2828:
2824:
2820:
2816:
2812:
2808:
2801:
2793:
2789:
2784:
2779:
2775:
2771:
2767:
2763:
2759:
2752:
2744:
2740:
2735:
2730:
2726:
2722:
2718:
2714:
2710:
2703:
2695:
2691:
2686:
2681:
2677:
2673:
2669:
2665:
2661:
2654:
2646:
2642:
2637:
2632:
2627:
2622:
2618:
2614:
2610:
2606:
2602:
2595:
2587:
2583:
2578:
2573:
2569:
2565:
2561:
2554:
2546:
2542:
2537:
2532:
2528:
2524:
2520:
2516:
2512:
2505:
2497:
2493:
2489:
2485:
2481:
2477:
2473:
2469:
2462:
2460:
2451:
2447:
2442:
2437:
2433:
2429:
2425:
2421:
2417:
2410:
2408:
2399:
2395:
2391:
2387:
2383:
2379:
2375:
2371:
2367:
2360:
2352:
2348:
2343:
2338:
2333:
2328:
2324:
2320:
2316:
2309:
2301:
2297:
2292:
2287:
2283:
2279:
2275:
2271:
2267:
2260:
2252:
2248:
2243:
2238:
2234:
2230:
2226:
2222:
2218:
2211:
2203:
2199:
2194:
2189:
2185:
2181:
2177:
2173:
2169:
2165:
2161:
2154:
2146:
2142:
2137:
2132:
2128:
2124:
2120:
2116:
2112:
2108:
2104:
2097:
2089:
2085:
2080:
2075:
2071:
2067:
2063:
2059:
2055:
2048:
2040:
2036:
2032:
2028:
2024:
2020:
2016:
2012:
2008:
2004:
1997:
1989:
1985:
1980:
1975:
1970:
1965:
1961:
1957:
1953:
1946:
1938:
1934:
1929:
1924:
1920:
1916:
1912:
1908:
1904:
1897:
1889:
1885:
1880:
1875:
1871:
1867:
1863:
1859:
1855:
1848:
1840:
1836:
1831:
1826:
1822:
1818:
1814:
1810:
1806:
1799:
1791:
1787:
1782:
1777:
1772:
1767:
1763:
1759:
1755:
1751:
1747:
1740:
1732:
1728:
1724:
1720:
1716:
1712:
1708:
1704:
1697:
1689:
1685:
1681:
1677:
1673:
1669:
1665:
1661:
1654:
1646:
1642:
1637:
1632:
1628:
1624:
1620:
1616:
1612:
1608:
1604:
1597:
1589:
1585:
1581:
1577:
1572:
1567:
1563:
1559:
1555:
1548:
1540:
1536:
1531:
1526:
1522:
1518:
1514:
1510:
1506:
1502:
1498:
1491:
1489:
1480:
1476:
1471:
1466:
1462:
1458:
1454:
1450:
1446:
1442:
1438:
1431:
1429:
1420:
1416:
1412:
1408:
1404:
1400:
1393:
1385:
1381:
1376:
1371:
1367:
1363:
1359:
1355:
1351:
1344:
1336:
1332:
1327:
1322:
1317:
1312:
1307:
1302:
1298:
1294:
1290:
1288:
1279:
1271:
1267:
1263:
1259:
1255:
1251:
1247:
1243:
1236:
1234:
1225:
1221:
1217:
1213:
1209:
1205:
1201:
1197:
1190:
1182:
1178:
1174:
1170:
1166:
1162:
1158:
1154:
1147:
1139:
1135:
1130:
1125:
1121:
1117:
1112:
1107:
1103:
1099:
1095:
1088:
1080:
1076:
1071:
1066:
1062:
1058:
1054:
1050:
1046:
1039:
1031:
1027:
1023:
1019:
1014:
1009:
1005:
1001:
997:
990:
982:
978:
973:
968:
964:
960:
956:
952:
948:
941:
939:
937:
935:
926:
922:
918:
914:
910:
906:
902:
898:
894:
890:
883:
879:
869:
866:
865:
859:
857:
852:
850:
846:
841:
832:
830:
826:
821:
817:
813:
803:
801:
797:
793:
789:
785:
780:
776:
772:
768:
764:
756:
750:
748:
744:
740:
736:
732:
728:
723:
719:
718:
711:
704:
698:
696:
686:
677:
675:
670:
666:
665:
660:
656:
652:
647:
645:
641:
637:
633:
629:
625:
621:
617:
613:
603:
601:
597:
593:
589:
584:
580:
576:
572:
571:
566:
556:
554:
550:
546:
542:
538:
534:
533:hybridization
531:
530:
525:
521:
517:
513:
509:
505:
501:
497:
496:Dam methylase
493:
489:
485:
481:
477:
473:
468:
466:
463:
459:
456:
455:
450:
448:
443:
442:enhancer trap
433:
431:
427:
426:transcription
423:
419:
409:
400:
398:
394:
390:
386:
382:
378:
374:
371:
367:
363:
345:
342:
338:
337:Enhanceosomes
335:
334:
333:
325:
323:
319:
315:
314:Enhancer RNAs
310:
308:
304:
300:
294:
290:
287:
283:
279:
274:
270:
266:
257:
253:
248:
244:
240:
239:messenger RNA
236:
232:
228:
224:
215:
213:
209:
204:
202:
198:
194:
190:
189:polymorphisms
186:
182:
178:
174:
173:transcription
170:
165:
163:
159:
155:
151:
147:
143:
139:
135:
125:
123:
119:
115:
111:
106:
104:
102:
97:
93:
89:
88:transcription
85:
81:
77:
73:
69:
65:
54:
51:
48:
45:
42:
39:
36:
35:
30:
23:
19:
4538:
4212:
4140:
4136:
4126:
4101:
4097:
4053:
4049:
4039:
4004:
4000:
3990:
3947:
3943:
3933:
3898:
3894:
3884:
3849:
3845:
3835:
3800:
3796:
3786:
3741:
3737:
3727:
3692:
3688:
3678:
3637:
3633:
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