Editing Promoter (genetics)

{{Short description|Region of DNA encouraging transcription}}
[[File:Lac Operon.svg|thumb|250px|
{{legend|yellow|''1'':&nbsp;[[RNA Polymerase]]}}
{{legend|green|''2'':&nbsp;[[Repressor]]}}
{{legend|orange|''3'':&nbsp;[[Promoter (genetics)|Promoter]]}}
{{legend|red|''4'':&nbsp;[[Operon|Operator]]}}
{{legend|white|''5'':&nbsp;[[Lactose]]}}
{{legend|cyan|''6'':&nbsp;lacZ, ''7'':&nbsp;lacY, ''8'':&nbsp;lacA.}}
'''Top''': The transcription of the gene is turned off. There is no lactose to inhibit the repressor, so the repressor binds to the operator, which obstructs the RNA polymerase from binding to the promoter and making the mRNA encoding the lactase gene.
<br>
'''Bottom''': The gene is turned on. Lactose is inhibiting the repressor, allowing the RNA polymerase to bind with the promoter and express the genes, which synthesize lactase. Eventually, the lactase will digest all of the lactose, until there is none to bind to the repressor. The repressor will then bind to the operator, stopping the manufacture of lactase.]]

In [[genetics]], a '''promoter''' is a sequence of [[DNA]] to which [[protein]]s bind to initiate [[transcription (genetics)|transcription]] of a single [[RNA]] transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein ([[mRNA]]), or can have a function in and of itself, such as [[tRNA]] or [[rRNA]]. Promoters are located near the transcription start sites of genes, [[Upstream and downstream (DNA)|upstream]] on the DNA (towards the [[Directionality (molecular biology)#5′-end|5' region]] of the [[sense strand]]).
Promoters can be about 100–1000 [[base pairs]] long, the sequence of which is highly dependent on the gene and product of transcription, type or class of [[RNA polymerase]] recruited to the site, and species of organism.<ref>{{cite web| vauthors = Sharan R |date=4 January 2007|title=Analysis of Biological Networks: Transcriptional Networks – Promoter Sequence Analysis|url=http://www.cs.tau.ac.il/~roded/courses/bnet-a06/lec11.pdf|publisher=Tel Aviv University|access-date=30 December 2012}}</ref><ref name=":0">{{cite journal | vauthors = LaFleur TL, Hossain A, Salis HM | title = Automated model-predictive design of synthetic promoters to control transcriptional profiles in bacteria | journal = Nature Communications | volume = 13 | issue = 1 | pages = 5159 | date = September 2022 | pmid = 36056029 | pmc = 9440211 | doi = 10.1038/s41467-022-32829-5 | bibcode = 2022NatCo..13.5159L }}</ref>

==Overview==
For transcription to take place, the enzyme that synthesizes RNA, known as [[RNA polymerase]], must attach to the DNA near a gene. Promoters contain specific DNA sequences such as [[response elements]] that provide a secure initial binding site for RNA polymerase and for proteins called [[transcription factors]] that recruit RNA polymerase. These transcription factors have specific [[Activator (genetics)|activator]] or [[repressor]] sequences of corresponding nucleotides that attach to specific promoters and regulate gene expression.{{cn|date=June 2024}}

;In [[bacteria]]: The promoter is recognized by RNA polymerase and an associated [[sigma factor]], which in turn are often brought to the promoter DNA by an activator protein's binding to its own [[DNA binding site]] nearby.
;In [[eukaryotes]]: The process is more complicated, and at least seven different factors are necessary for the binding of an [[RNA polymerase II]] to the promoter.
;In [[archaea]]: The promoter resembles a eukaryotic one, though much simplified. It contains BRE and TATA elements and are recognized by TFB and TBP.<ref name="pmid33112729">{{cite journal |last1=Wenck |first1=BR |last2=Santangelo |first2=TJ |title=Archaeal transcription. |journal=Transcription |date=October 2020 |volume=11 |issue=5 |pages=199–210 |doi=10.1080/21541264.2020.1838865 |pmid=33112729 |pmc=7714419}}</ref>

Promoters represent critical elements that can work in concert with other regulatory regions ([[Enhancer (genetics)|enhancer]]s, [[silencer (DNA)|silencers]], boundary elements/[[Insulator (genetics)|insulators]]) to direct the level of transcription of a given gene.
A promoter is induced in response to changes in abundance or conformation of regulatory proteins in a cell, which enable activating transcription factors to recruit RNA polymerase.<ref name="pmid24825771">{{cite journal | vauthors = Yaniv M | title = Chromatin remodeling: from transcription to cancer | journal = Cancer Genetics | volume = 207 | issue = 9 | pages = 352–7 | date = September 2014 | pmid = 24825771 | doi = 10.1016/j.cancergen.2014.03.006 }}</ref><ref name="pmid16380379">{{cite journal | vauthors = Civas A, Génin P, Morin P, Lin R, Hiscott J | title = Promoter organization of the interferon-A genes differentially affects virus-induced expression and responsiveness to TBK1 and IKKepsilon | journal = The Journal of Biological Chemistry | volume = 281 | issue = 8 | pages = 4856–66 | date = February 2006 | pmid = 16380379 | doi = 10.1074/jbc.M506812200 | doi-access = free }}</ref>

Given the short sequences of most promoter elements, promoters can rapidly evolve from random sequences. For instance, in [[Escherichia coli|''E. coli'']], ~60% of random sequences can evolve expression levels comparable to the wild-type [[Lac operon|lac promoter]] with only one mutation, and that ~10% of random sequences can serve as active promoters even without evolution.<ref>{{cite journal |vauthors=Yona AH, Alm EJ, Gore J |date=April 2018 |title=Random sequences rapidly evolve into de novo promoters |journal=Nature Communications |language=En |volume=9 |issue=1 |pages=1530 |bibcode=2018NatCo...9.1530Y |doi=10.1038/s41467-018-04026-w |pmc=5906472 |pmid=29670097}}</ref>

== Identification of relative location ==
As promoters are typically immediately adjacent to the gene in question, positions in the promoter are designated relative to the [[transcription start site|transcriptional start site]], where transcription of DNA begins for a particular gene (i.e., positions upstream are negative numbers counting back from -1, for example -100 is a position 100 base pairs upstream).{{cn|date=June 2024}}

== Elements ==
{{anchor|Promoter_elements}}

=== Bacterial ===
In [[bacteria]], the promoter contains two short sequence elements approximately 10 ([[Pribnow box|Pribnow Box]]) and 35 nucleotides ''upstream'' from the [[transcription start site]].<ref name=":0" />
* The sequence at -10 (the -10 element) has the [[consensus sequence]] TATAAT.
* The sequence at -35 (the -35 element) has the consensus sequence TTGACA.
* The above consensus sequences, while conserved on average, are not found intact in most promoters. On average, only 3 to 4 of the 6 base pairs in each consensus sequence are found in any given promoter. Few natural promoters have been identified to date that possess intact consensus sequences at both the -10 and -35; artificial promoters with complete conservation of the -10 and -35 elements have been found to transcribe at lower frequencies than those with a few mismatches with the consensus.
* The optimal spacing between the -35 and -10 sequences is 17 bp. The spacer sequence affects promoter strength by up to 600-fold.<ref name=kuo25/>
* Some promoters contain one or more upstream promoter element (UP element) subsites<ref name="Ross 1998">{{cite journal | vauthors = Ross W, Gosink KK, Salomon J, Igarashi K, Zou C, Ishihama A, Severinov K, Gourse RL | display-authors = 6 | title = A third recognition element in bacterial promoters: DNA binding by the alpha subunit of RNA polymerase | journal = Science | volume = 262 | issue = 5138 | pages = 1407–1413 | date = November 1993 | pmid = 8248780 | doi = 10.1126/science.8248780 | bibcode = 1993Sci...262.1407R }}</ref> ([[consensus sequence]] 5'-AAAAAARNR-3' when centered in the -42 region; consensus sequence 5'-AWWWWWTTTTT-3' when centered in the -52 region; W = A or T; R = A or G; N = any base).<ref>{{cite journal | vauthors = Estrem ST, Ross W, Gaal T, Chen ZW, Niu W, Ebright RH, Gourse RL | title = Bacterial promoter architecture: subsite structure of UP elements and interactions with the carboxy-terminal domain of the RNA polymerase alpha subunit | journal = Genes & Development | volume = 13 | issue = 16 | pages = 2134–2147 | date = August 1999 | pmid = 10465790 | pmc = 316962 | doi = 10.1101/gad.13.16.2134 }}</ref>
* The transcription start site has the consensus sequence YRY.<ref name=kuo25>{{Cite journal| doi = 10.1101/2025.01.23.634641| pages = 2025–01.23.634641| last1 = Kuo| first1 = Syue-Ting| last2 = Chang| first2 = Joshua Kevin| last3 = Chang| first3 = Clara| last4 = Shen| first4 = Wei-Yi| last5 = Hsu| first5 = Christine| last6 = Lai| first6 = Sheng-Wen| last7 = Chou| first7 = Hsin-Hung David| title = Unravel the start element and promoter architecture across the domain Bacteria| journal = bioRxiv| date = 2025-01-01}}</ref>

The above promoter sequences are recognized only by RNA polymerase [[holoenzyme]] containing [[sigma-70]]. RNA polymerase holoenzymes containing other sigma factors recognize different core promoter sequences.

 ← upstream                                                                     downstream →
 5'-XXXXXXXPPPPPPXXXXXXPPPPPPXXXXGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGXXXX-3'
            -35       -10       Gene to be transcribed

====Probability of occurrence of each nucleotide====
  for -10 sequence
  T    A    T    A    A   T
 77%  76%  60%  61%  56%  82%

  for -35 sequence
  T    T    G    A    C    A
 69%  79%  61%  56%  54%  54%

==== Bidirectional (prokaryotic) ====
Promoters can be very closely located in the DNA. Such "closely spaced promoters" have been observed in the DNAs of all life forms, from humans<ref name="Adachi_2002">{{cite journal | vauthors = Adachi N, Lieber MR | title = Bidirectional gene organization: a common architectural feature of the human genome | journal = Cell | volume = 109 | issue = 7 | pages = 807–809 | date = June 2002 | pmid = 12110178 | doi = 10.1016/S0092-8674(02)00758-4 | doi-access = free }}</ref> to prokaryotes<ref name=" Herbert_1986">{{cite journal | vauthors = Herbert M, Kolb A, Buc H | title = Overlapping promoters and their control in Escherichia coli: the gal case | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 9 | pages = 2807–2811 | date = May 1986 | pmid = 3010319 | pmc = 323395 | doi = 10.1073/pnas.83.9.2807 | doi-access = free | bibcode = 1986PNAS...83.2807H }}</ref> and are highly conserved.<ref name=" Korbel_2004">{{cite journal | vauthors = Korbel JO, Jensen LJ, von Mering C, Bork P | title = Analysis of genomic context: prediction of functional associations from conserved bidirectionally transcribed gene pairs | journal = Nature Biotechnology | volume = 22 | issue = 7 | pages = 911–917 | date = July 2004 | pmid = 15229555 | doi = 10.1038/nbt988 | s2cid = 3546895 | doi-access =  }}</ref> Therefore, they may provide some (presently unknown) advantages.
These pairs of promoters can be positioned in divergent, tandem, and convergent directions. They can also be regulated by transcription factors and differ in various features, such as the nucleotide distance between them, the two promoter strengths, etc.
The most important aspect of two closely spaced promoters is that they will, most likely, interfere with each other. Several studies have explored this using both analytical and stochastic models.<ref name=" Sneppen_2005">{{cite journal | vauthors = Sneppen K, Dodd IB, Shearwin KE, Palmer AC, Schubert RA, Callen BP, Egan JB | title = A mathematical model for transcriptional interference by RNA polymerase traffic in Escherichia coli | journal = Journal of Molecular Biology | volume = 346 | issue = 2 | pages = 399–409 | date = February 2005 | pmid = 15670592 | doi = 10.1016/j.jmb.2004.11.075 | doi-access =  }}</ref><ref name=" Martins_2012">{{cite journal | vauthors = Martins L, Mäkelä J, Häkkinen A, Kandhavelu M, Yli-Harja O, Fonseca JM, Ribeiro AS | title = Dynamics of transcription of closely spaced promoters in Escherichia coli, one event at a time | journal = Journal of Theoretical Biology | volume = 301 | pages = 83–94 | date = May 2012 | pmid = 22370562 | doi = 10.1016/j.jtbi.2012.02.015 | doi-access =  | bibcode = 2012JThBi.301...83M }}</ref><ref name="Hakkinen_2016">{{cite journal | vauthors = Häkkinen A, Oliveira SM, Neeli-Venkata R, Ribeiro AS | title = Transcription closed and open complex formation coordinate expression of genes with a shared promoter region | journal = Journal of the Royal Society, Interface | volume = 16 | issue = 161 | pages = 20190507 | date = December 2019 | pmid = 31822223 | pmc = 6936044 | doi = 10.1098/rsif.2019.0507 | doi-access = free }}</ref> There are also studies that measured gene expression in synthetic genes or from one to a few genes controlled by bidirectional promoters.<ref name=" Bordoy_2016">{{cite journal | vauthors = Bordoy AE, Varanasi US, Courtney CM, Chatterjee A | title = Transcriptional Interference in Convergent Promoters as a Means for Tunable Gene Expression | journal = ACS Synthetic Biology | volume = 5 | issue = 12 | pages = 1331–1341 | date = December 2016 | pmid = 27346626 | doi = 10.1021/acssynbio.5b00223 | doi-access =  }}</ref>

[[File:These are two tandem promoters with occlusion – March 2022 TP686.png|thumb|Depiction the phenomenon of interference between tandem promoters. Figure created with BioRender.com]]

More recently, one study measured most genes controlled by tandem promoters in ''E. coli''.<ref name=" Chauhan_2022">{{cite journal | vauthors = Chauhan V, Bahrudeen MN, Palma CS, Baptista IS, Almeida BL, Dash S, Kandavalli V, Ribeiro AS | display-authors = 6 | title = Analytical kinetic model of native tandem promoters in E. coli | journal = PLOS Computational Biology | volume = 18 | issue = 1 | pages = e1009824 | date = January 2022 | pmid = 35100257 | pmc = 8830795 | doi = 10.1371/journal.pcbi.1009824 | doi-access = free | bibcode = 2022PLSCB..18E9824C }}</ref> In that study, two main forms of interference were measured. One is when an RNAP is on the downstream promoter, blocking the movement of RNAPs elongating from the upstream promoter. The other is when the two promoters are so close that when an RNAP sits on one of the promoters, it blocks any other RNAP from reaching the other promoter. These events are possible because the RNAP occupies several nucleotides when bound to the DNA, including in transcription start sites.
Similar events occur when the promoters are in divergent and convergent formations. The possible events also depend on the distance between them.

=== Eukaryotic ===
Gene promoters are typically located upstream of the gene and can have regulatory elements several kilobases away from the transcriptional start site (enhancers). In eukaryotes, the transcriptional complex can cause the DNA to bend back on itself, which allows for placement of regulatory sequences far from the actual site of transcription. Eukaryotic RNA-polymerase-II-dependent promoters can contain a [[TATA box]] ([[consensus sequence]] TATAAA), which is recognized by the [[general transcription factor]] [[TATA-binding protein]] (TBP); and a [[B recognition element]] (BRE), which is recognized by the general transcription factor [[TFIIB]].<ref name="Smale2003" /><ref>{{cite journal | vauthors = Gershenzon NI, Ioshikhes IP | title = Synergy of human Pol II core promoter elements revealed by statistical sequence analysis | journal = Bioinformatics | volume = 21 | issue = 8 | pages = 1295–1300 | date = April 2005 | pmid = 15572469 | doi = 10.1093/bioinformatics/bti172 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lagrange T, Kapanidis AN, Tang H, Reinberg D, Ebright RH | title = New core promoter element in RNA polymerase II-dependent transcription: sequence-specific DNA binding by transcription factor IIB | journal = Genes & Development | volume = 12 | issue = 1 | pages = 34–44 | date = January 1998 | pmid = 9420329 | pmc = 316406 | doi = 10.1101/gad.12.1.34 }}</ref> The TATA element and BRE typically are located close to the transcriptional start site (typically within 30 to 40 base pairs).

Eukaryotic promoter regulatory sequences typically bind proteins called transcription factors that are involved in the formation of the transcriptional complex. An example is the [[E-box]] (sequence CACGTG), which binds transcription factors in the [[basic helix-loop-helix]] (bHLH) family (e.g. [[BMAL1-Clock]], [[cMyc]]).<ref>{{cite journal | vauthors = Levine M, Tjian R | title = Transcription regulation and animal diversity | journal = Nature | volume = 424 | issue = 6945 | pages = 147–151 | date = July 2003 | pmid = 12853946 | doi = 10.1038/nature01763 | s2cid = 4373712 | bibcode = 2003Natur.424..147L }}</ref> Some promoters that are targeted by multiple transcription factors might achieve a hyperactive state, leading to increased transcriptional activity.<ref name=Liefke2015>{{cite journal | vauthors = Liefke R, Windhof-Jaidhauser IM, Gaedcke J, Salinas-Riester G, Wu F, Ghadimi M, Dango S | title = The oxidative demethylase ALKBH3 marks hyperactive gene promoters in human cancer cells | journal = Genome Medicine | volume = 7 | issue = 1 | pages = 66 | date = June 2015 | pmid = 26221185 | pmc = 4517488 | doi = 10.1186/s13073-015-0180-0 | doi-access = free }}</ref>
* Core promoter – the minimal portion of the promoter required to properly initiate transcription<ref name="Smale2003" >{{cite journal | vauthors = Smale ST, Kadonaga JT | title = The RNA polymerase II core promoter | journal = Annual Review of Biochemistry | volume = 72 | pages = 449–479 | year = 2003 | pmid = 12651739 | doi = 10.1146/annurev.biochem.72.121801.161520 }}</ref>
** Includes the transcription start site (TSS) and elements directly upstream
** A binding site for RNA polymerase
*** [[RNA polymerase I]]: transcribes genes encoding 18S, 5.8S and 28S [[ribosomal RNA]]s
*** [[RNA polymerase II]]: transcribes genes encoding [[messenger RNA]] and certain [[small nuclear RNA]]s and [[microRNA]]
*** [[RNA polymerase III]]: transcribes genes encoding [[transfer RNA]], [[5S ribosomal RNA|5s ribosomal RNAs]] and other small RNAs
** General transcription factor binding sites, e.g. [[TATA box]], [[B recognition element]].
** Many other elements/motifs may be present. There is no such thing as a set of "universal elements" found in every core promoter.<ref name="pmid19682982">{{cite journal | vauthors = Juven-Gershon T, Kadonaga JT | title = Regulation of gene expression via the core promoter and the basal transcriptional machinery | journal = Developmental Biology | volume = 339 | issue = 2 | pages = 225–229 | date = March 2010 | pmid = 19682982 | pmc = 2830304 | doi = 10.1016/j.ydbio.2009.08.009 }}</ref>
* Proximal promoter – the proximal sequence upstream of the gene that tends to contain primary regulatory elements
** Approximately 250 base pairs upstream of the start site
** Specific [[transcription factor binding site]]s
* [[Distal promoter]] – the distal sequence upstream of the gene that may contain additional regulatory elements, often with a weaker influence than the proximal promoter
** Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)
** Specific transcription factor binding sites

====Mammalian promoters====
{{cleanup section|reason=Text about mammals highly duplicated among uses of the same picture -- can we make a "canonical" version and redirect people there?|date=September 2021}}
[[File:Regulation of transcription in mammals.jpg|thumb|left|500px| '''Regulation of transcription in mammals'''. An active [[Enhancer (genetics)|enhancer]] regulatory region is enabled to interact with the promoter region of its target [[gene]] by formation of a chromosome loop.  This can initiate [[messenger RNA]] (mRNA) synthesis by [[RNA polymerase II]] (RNAP II) bound to the promoter at the [[Transcription (biology)|transcription start site]] 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 [[transcription factor]]s bind to DNA sequence motifs on the enhancer. [[General transcription factor]]s bind to the promoter. When a transcription factor is activated by a signal (here indicated as [[phosphorylation]] 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 (coactivator)]] (a complex consisting of about 26 proteins in an interacting structure) communicates regulatory signals from the enhancer DNA-bound transcription factors to the promoter.]]

Up-regulated expression of genes in mammals is initiated when signals are transmitted to the promoters associated with the genes. Promoter DNA sequences may include different elements such as [[CpG site|CpG islands]] (present in about 70% of promoters), a [[TATA box]] (present in about 24% of promoters), [[Initiator element|initiator (Inr)]] (present in about 49% of promoters), upstream and downstream TFIIB recognition elements (BREu and BREd) (present in about 22% of promoters), and downstream core promoter element (DPE) (present in about 12% of promoters).<ref name=Yang>{{cite journal | vauthors = Yang C, Bolotin E, Jiang T, Sladek FM, Martinez E | title = Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters | journal = Gene | volume = 389 | issue = 1 | pages = 52–65 | date = March 2007 | pmid = 17123746 | pmc = 1955227 | doi = 10.1016/j.gene.2006.09.029 }}</ref> The presence of multiple [[DNA methylation|methylated CpG sites]] in CpG islands of promoters causes stable silencing of genes.<ref name=Bird>{{cite journal | vauthors = Bird A | title = DNA methylation patterns and epigenetic memory | journal = Genes & Development | volume = 16 | issue = 1 | pages = 6–21 | date = January 2002 | pmid = 11782440 | doi = 10.1101/gad.947102 | doi-access = free }}</ref> However, the presence or absence of the other elements have relatively small effects on gene expression in experiments.<ref name=Weingarten-Gabbay>{{cite journal | vauthors = Weingarten-Gabbay S, Nir R, Lubliner S, Sharon E, Kalma Y, Weinberger A, Segal E | title = Systematic interrogation of human promoters | journal = Genome Research | volume = 29 | issue = 2 | pages = 171–183 | date = February 2019 | pmid = 30622120 | pmc = 6360817 | doi = 10.1101/gr.236075.118 }}</ref> Two sequences, the TATA box and Inr, caused small but significant increases in expression (45% and 28% increases, respectively). The BREu and the BREd elements significantly decreased expression by 35% and 20%, respectively, and the DPE element had no detected effect on expression.<ref name=Weingarten-Gabbay />

[[Cis-regulatory element|Cis-regulatory modules]] that are localized 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 cis-regulatory module.<ref name=Beagan>{{cite journal | vauthors = Beagan JA, Pastuzyn ED, Fernandez LR, Guo MH, Feng K, Titus KR, Chandrashekar H, Shepherd JD, Phillips-Cremins JE | display-authors = 6 | title = Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression | journal = Nature Neuroscience | volume = 23 | issue = 6 | pages = 707–717 | date = June 2020 | pmid = 32451484 | pmc = 7558717 | doi = 10.1038/s41593-020-0634-6 }}</ref> These cis-regulatory modules include [[Enhancer (genetics)|enhancers]], [[Silencer (genetics)|silencers]], [[Insulator (genetics)|insulators]] and tethering elements.<ref name="pmid33102493">{{cite journal | vauthors = Verheul TC, van Hijfte L, Perenthaler E, Barakat TS | title = The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1 | journal = Frontiers in Cell and Developmental Biology | volume = 8 | issue =  | pages = 592164 | date = 2020 | pmid = 33102493 | pmc = 7554316 | doi = 10.3389/fcell.2020.592164 | doi-access = free }}</ref> Among this constellation of elements, enhancers and their associated [[transcription factors]] have a leading role in the regulation of gene expression.<ref name="pmid22868264">{{cite journal | vauthors = Spitz F, Furlong EE | title = Transcription factors: from enhancer binding to developmental control | journal = Nature Reviews. Genetics | volume = 13 | issue = 9 | pages = 613–626 | date = September 2012 | pmid = 22868264 | doi = 10.1038/nrg3207 | s2cid = 205485256 }}</ref>

[[Enhancer (genetics)|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.<ref name=Schoenfelder>{{cite journal | vauthors = Schoenfelder S, Fraser P | title = Long-range enhancer-promoter contacts in gene expression control | journal = Nature Reviews. Genetics | volume = 20 | issue = 8 | pages = 437–455 | date = August 2019 | pmid = 31086298 | doi = 10.1038/s41576-019-0128-0 | s2cid = 152283312 }}</ref>  In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to promoters.<ref name=Beagan />  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.<ref name=Schoenfelder />

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 [[CTCF]] or [[YY1]]), 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).<ref name="pmid29224777">{{cite journal | vauthors = Weintraub AS, Li CH, Zamudio AV, Sigova AA, Hannett NM, Day DS, Abraham BJ, Cohen MA, Nabet B, Buckley DL, Guo YE, Hnisz D, Jaenisch R, Bradner JE, Gray NS, Young RA | display-authors = 6 | title = YY1 Is a Structural Regulator of Enhancer-Promoter Loops | journal = Cell | volume = 171 | issue = 7 | pages = 1573–1588.e28 | date = December 2017 | pmid = 29224777 | pmc = 5785279 | doi = 10.1016/j.cell.2017.11.008 }}</ref>  Several cell function specific transcription factors (there are about 1,600 transcription factors in a human cell<ref name="pmid29425488">{{cite journal | vauthors = Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X, Taipale J, Hughes TR, Weirauch MT | display-authors = 6 | title = The Human Transcription Factors | journal = Cell | volume = 172 | issue = 4 | pages = 650–665 | date = February 2018 | pmid = 29425488 | doi = 10.1016/j.cell.2018.01.029 | doi-access = free }}</ref>) generally bind to specific motifs on an enhancer<ref name="pmid29987030">{{cite journal | vauthors = Grossman SR, Engreitz J, Ray JP, Nguyen TH, Hacohen N, Lander ES | title = Positional specificity of different transcription factor classes within enhancers | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 30 | pages = E7222–E7230 | date = July 2018 | pmid = 29987030 | pmc = 6065035 | doi = 10.1073/pnas.1804663115 | bibcode = 2018PNAS..115E7222G | doi-access = free }}</ref> 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.  [[Mediator (coactivator)]] (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.<ref name="pmid25693131">{{cite journal | vauthors = Allen BL, Taatjes DJ | title = The Mediator complex: a central integrator of transcription | journal = Nature Reviews. Molecular Cell Biology | volume = 16 | issue = 3 | pages = 155–166 | date = March 2015 | pmid = 25693131 | pmc = 4963239 | doi = 10.1038/nrm3951 }}</ref>

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.<ref name="pmid29378788">{{cite journal | vauthors = Mikhaylichenko O, Bondarenko V, Harnett D, Schor IE, Males M, Viales RR, Furlong EE | title = The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription | journal = Genes & Development | volume = 32 | issue = 1 | pages = 42–57 | date = January 2018 | pmid = 29378788 | pmc = 5828394 | doi = 10.1101/gad.308619.117 }}</ref>  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).<ref name="pmid12514134">{{cite journal | vauthors = Li QJ, Yang SH, Maeda Y, Sladek FM, Sharrocks AD, Martins-Green M | title = MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300 | journal = The EMBO Journal | volume = 22 | issue = 2 | pages = 281–291 | date = January 2003 | pmid = 12514134 | pmc = 140103 | doi = 10.1093/emboj/cdg028 }}</ref>  An activated enhancer begins transcription of its RNA before activating a promoter to initiate transcription of messenger RNA from its target gene.<ref name="pmid32810208">{{cite journal | vauthors = Carullo NV, Phillips Iii RA, Simon RC, Soto SA, Hinds JE, Salisbury AJ, Revanna JS, Bunner KD, Ianov L, Sultan FA, Savell KE, Gersbach CA, Day JJ | display-authors = 6 | title = Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems | journal = Nucleic Acids Research | volume = 48 | issue = 17 | pages = 9550–9570 | date = September 2020 | pmid = 32810208 | pmc = 7515708 | doi = 10.1093/nar/gkaa671 }}</ref>

====Bidirectional (mammalian)====
Bidirectional promoters are short (<1 kbp) intergenic regions of [[DNA]] between the 5' ends of the [[genes]] in a bidirectional gene pair.<ref name="Trinklein">{{cite journal | vauthors = Trinklein ND, Aldred SF, Hartman SJ, Schroeder DI, Otillar RP, Myers RM | title = An abundance of bidirectional promoters in the human genome | journal = Genome Research | volume = 14 | issue = 1 | pages = 62–66 | date = January 2004 | pmid = 14707170 | pmc = 314279 | doi = 10.1101/gr.1982804 }}</ref> A "bidirectional gene pair" refers to two adjacent genes coded on opposite strands, with their 5' ends oriented toward one another.<ref>{{cite journal | vauthors = Yang MQ, Koehly LM, Elnitski LL | title = Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes | journal = PLOS Computational Biology | volume = 3 | issue = 4 | pages = e72 | date = April 2007 | pmid = 17447839 | pmc = 1853124 | doi = 10.1371/journal.pcbi.0030072 | bibcode = 2007PLSCB...3...72Y | doi-access = free }}</ref> The two genes are often functionally related, and modification of their shared promoter region allows them to be co-regulated and thus co-expressed.<ref>{{cite journal | vauthors = Adachi N, Lieber MR | title = Bidirectional gene organization: a common architectural feature of the human genome | journal = Cell | volume = 109 | issue = 7 | pages = 807–809 | date = June 2002 | pmid = 12110178 | doi = 10.1016/S0092-8674(02)00758-4 | s2cid = 8556921 | doi-access = free }}</ref> Bidirectional promoters are a common feature of [[mammal]]ian [[genome]]s.<ref>{{cite journal | vauthors = Koyanagi KO, Hagiwara M, Itoh T, Gojobori T, Imanishi T | title = Comparative genomics of bidirectional gene pairs and its implications for the evolution of a transcriptional regulation system | journal = Gene | volume = 353 | issue = 2 | pages = 169–176 | date = July 2005 | pmid = 15944140 | doi = 10.1016/j.gene.2005.04.027 }}</ref> About 11% of human genes are bidirectionally paired.<ref name="Trinklein" />

Bidirectionally paired genes in the [[Gene Ontology]] database shared at least one database-assigned functional category with their partners 47% of the time.<ref>{{cite journal | vauthors = Liu B, Chen J, Shen B | title = Genome-wide analysis of the transcription factor binding preference of human bi-directional promoters and functional annotation of related gene pairs | journal = BMC Systems Biology | volume = 5 | issue = Suppl 1 | pages = S2 | date = May 2011 | pmid = 21689477 | pmc = 3121118 | doi = 10.1186/1752-0509-5-S1-S2 | doi-access = free }}</ref> [[Microarray]] analysis has shown bidirectionally paired genes to be co-expressed to a higher degree than random genes or neighboring unidirectional genes.<ref name="Trinklein" /> Although co-expression does not necessarily indicate co-regulation, [[methylation]] of bidirectional promoter regions has been shown to downregulate both genes, and demethylation to upregulate both genes.<ref name="Shu">{{cite journal | vauthors = Shu J, Jelinek J, Chang H, Shen L, Qin T, Chung W, Oki Y, Issa JP | display-authors = 6 | title = Silencing of bidirectional promoters by DNA methylation in tumorigenesis | journal = Cancer Research | volume = 66 | issue = 10 | pages = 5077–5084 | date = May 2006 | pmid = 16707430 | doi = 10.1158/0008-5472.CAN-05-2629 | doi-access = free }}</ref> There are exceptions to this, however. In some cases (about 11%), only one gene of a bidirectional pair is expressed.<ref name="Trinklein" /> In these cases, the promoter is implicated in suppression of the non-expressed gene. The mechanism behind this could be competition for the same polymerases, or [[chromatin]] modification. Divergent transcription could shift [[nucleosomes]] to upregulate transcription of one gene, or remove bound transcription factors to downregulate transcription of one gene.<ref name="dx">{{cite journal | vauthors = Wei W, Pelechano V, Järvelin AI, Steinmetz LM | title = Functional consequences of bidirectional promoters | journal = Trends in Genetics | volume = 27 | issue = 7 | pages = 267–276 | date = July 2011 | pmid = 21601935 | pmc = 3123404 | doi = 10.1016/j.tig.2011.04.002 }}</ref>

Some functional classes of genes are more likely to be bidirectionally paired than others. Genes implicated in DNA repair are five times more likely to be regulated by bidirectional promoters than by unidirectional promoters. [[Chaperone proteins]] are three times more likely, and [[mitochondrial gene]]s are more than twice as likely. Many basic [[Housekeeping gene|housekeeping]] and cellular metabolic genes are regulated by bidirectional promoters.<ref name="Trinklein" />
The overrepresentation of bidirectionally paired DNA repair genes associates these promoters with [[cancer]]. Forty-five percent of human [[Somatic (biology)|somatic]] [[oncogenes]] seem to be regulated by bidirectional promoters – significantly more than non-cancer causing genes. Hypermethylation of the promoters between gene pairs [[WNT9A]]/CD558500, [[CTDSPL]]/BC040563, and [[KCNK15]]/BF195580 has been associated with tumors.<ref name="Shu" />

Certain sequence characteristics have been observed in bidirectional promoters, including a lack of [[TATA box]]es, an abundance of [[CpG site|CpG islands]], and a symmetry around the midpoint of dominant Cs and As on one side and Gs and Ts on the other. A motif with the consensus sequence of TCTCGCGAGA, also called the [[CGCG element]], was recently shown to drive PolII-driven bidirectional transcription in CpG islands.<ref>{{cite journal | vauthors = Mahpour A, Scruggs BS, Smiraglia D, Ouchi T, Gelman IH | title = A methyl-sensitive element induces bidirectional transcription in TATA-less CpG island-associated promoters | journal = PLOS ONE | volume = 13 | issue = 10 | pages = e0205608 | date = 2018-10-17 | pmid = 30332484 | pmc = 6192621 | doi = 10.1371/journal.pone.0205608 | doi-access = free | bibcode = 2018PLoSO..1305608M }}</ref> [[CCAAT box]]es are common, as they are in many promoters that lack TATA boxes. In addition, the [[Sequence motif|motifs]] NRF-1, [[GABPA]], [[YY1]], and ACTACAnnTCCC are represented in bidirectional promoters at significantly higher rates than in unidirectional promoters. The absence of TATA boxes in bidirectional promoters suggests that TATA boxes play a role in determining the directionality of promoters, but counterexamples of bidirectional promoters do possess TATA boxes and unidirectional promoters without them indicates that they cannot be the only factor.<ref>{{cite journal | vauthors = Lin JM, Collins PJ, Trinklein ND, Fu Y, Xi H, Myers RM, Weng Z | title = Transcription factor binding and modified histones in human bidirectional promoters | journal = Genome Research | volume = 17 | issue = 6 | pages = 818–827 | date = June 2007 | pmid = 17568000 | pmc = 1891341 | doi = 10.1101/gr.5623407 }}</ref>

Although the term "bidirectional promoter" refers specifically to promoter regions of [[mRNA]]-encoding genes, [[luciferase]] assays have shown that over half of human genes do not have a strong directional bias. Research suggests that [[non-coding RNAs]] are frequently associated with the promoter regions of mRNA-encoding genes. It has been hypothesized that the recruitment and initiation of [[RNA polymerase II]] usually begins bidirectionally, but divergent transcription is halted at a checkpoint later during elongation. Possible mechanisms behind this regulation include sequences in the promoter region, chromatin modification, and the spatial orientation of the DNA.<ref name="dx" />

=== Archaea ===
The archaeal promoter resembles an eukaryotic one: a TATA box (at -26/-27) and an upstream BRE (at -33/-34) are commonly found, binding to TBP and TFB (homolog of TFIIB).<ref name=pmid33112729/> There are also occasionally an initiator element (INR) near the transcription start site [TSS], and a promoter proximal element (PPE) between BRE-TATA and TSS. These two are not necessary, but enhance the strength of a promoter.<ref name="pmid34713600"/> TFE (homolog of [[TFIIE]]) promotes initiation at suboptimal promoter sequences.<ref name="pmid34713600"/> It binds between -10 and +1, near the Inr.<ref name=pmid33112729/>

Strict conservation of these motifs are not necessary, and many archaea with high GC% show "degenerated" TATA boxes. Rather, it's the energetic (duplex enthalpy, duplex stability) and structual (intrinsic curvature, bendability) features of the promoter that mainly matter.<ref name="pmid34713600">{{cite journal |last1=Martinez |first1=GS |last2=Sarkar |first2=S |last3=Kumar |first3=A |last4=Pérez-Rueda |first4=E |last5=de Avila E Silva |first5=S |title=Characterization of promoters in archaeal genomes based on DNA structural parameters. |journal=MicrobiologyOpen |date=October 2021 |volume=10 |issue=5 |pages=e1230 |doi=10.1002/mbo3.1230 |pmid=34713600|pmc=8553660 }}</ref>

== Subgenomic ==
A subgenomic promoter is a promoter added to a virus for a specific [[heterologous]] gene, resulting in the formation of mRNA for that gene alone. Many positive-sense [[RNA virus]]es produce these [[subgenomic mRNA]]s (sgRNA) as one of the common infection techniques used by these viruses and generally transcribe late viral genes. Subgenomic promoters range from 24 nucleotide ([[Sindbis virus]]) to over 100 nucleotides ([[Beet necrotic yellow vein virus]]) and are usually found upstream of the transcription start.<ref>{{cite journal | vauthors = Koev G, Miller WA | title = A positive-strand RNA virus with three very different subgenomic RNA promoters | journal = Journal of Virology | volume = 74 | issue = 13 | pages = 5988–5996 | date = July 2000 | pmid = 10846080 | pmc = 112095 | doi = 10.1128/jvi.74.13.5988-5996.2000 }}</ref>

== Detection ==
A wide variety of algorithms have been developed to facilitate detection of promoters in genomic sequence, and promoter prediction is a common element of many [[gene prediction]] methods. Many such tools have been developed.<ref>{{cite web |title=Online Analysis Tools - Promoters |url=https://molbiol-tools.ca/Promoters.htm |website=molbiol-tools.ca}}</ref> A bacterial promoter region is located before the -35 and -10 Consensus sequences. The closer the promoter region is to the consensus sequences the more often transcription of that gene will take place. There is not a set pattern for promoter regions as there are for consensus sequences.

One approach is to use a biophysical theory of why promoters work. For archaea, a combination of calculated energetic and structual features can detect promoters.<ref name="pmid34713600"/> For bacteria, a biophysical model that estimates RNAP-sigma70 binding probability can detect and estimate the strengths of promoters.<ref name=kuo25/>

Another approach is to use a pattern-matching program based on known promoters, from simple hand-crafted [[regular expression]]s to advanced [[machine learning]] methods such as decision trees, [[hidden Markov model]]s (HMM), and [[neural networks]]. YAPP, an 2000s eukaryotic core-promoter prediction program, uses HMM.<ref>{{cite web |title=YAPP Eukaryotic Core Promoter Predictor |url=https://www.bioinformatics.org/yapp/cgi-bin/yapp_intro.cgi |website=www.bioinformatics.org}}</ref> A 2017 publication predicts bacterial and eukaryotic promoters using a [[convolutional neural network]].<ref>{{cite journal |last1=Umarov |first1=RK |last2=Solovyev |first2=VV |title=Recognition of prokaryotic and eukaryotic promoters using convolutional deep learning neural networks. |journal=PLOS ONE |date=2017 |volume=12 |issue=2 |pages=e0171410 |doi=10.1371/journal.pone.0171410 |doi-access=free|pmid=28158264|pmc=5291440 }}</ref>

== Binding ==
{{See also|Promoter activity}}

The initiation of the transcription is a multistep sequential process that involves several mechanisms: promoter location, initial reversible binding of RNA polymerase, conformational changes in RNA polymerase, conformational changes in DNA, binding of nucleoside triphosphate  (NTP) to the functional RNA polymerase-promoter complex,  and nonproductive and productive initiation of RNA synthesis.<ref>{{cite journal | vauthors = deHaseth PL, Zupancic ML, Record MT | title = RNA polymerase-promoter interactions: the comings and goings of RNA polymerase | journal = Journal of Bacteriology | volume = 180 | issue = 12 | pages = 3019–3025 | date = June 1998 | pmid = 9620948 | pmc = 107799 | doi = 10.1128/jb.180.12.3019-3025.1998 }}</ref><ref name=":0" />

The promoter binding process is crucial in the understanding of the process of gene expression. Tuning synthetic genetic systems relies on precisely engineered synthetic promoters with known levels of transcription rates.<ref name=":0" />

=== Location ===
Although RNA polymerase [[holoenzyme]] shows high affinity to non-specific sites of the DNA, this characteristic does not allow us to clarify the process of promoter location.<ref name="pmid3308887">{{cite journal | vauthors = Singer P, Wu CW | title = Promoter search by Escherichia coli RNA polymerase on a circular DNA template | journal = The Journal of Biological Chemistry | volume = 262 | issue = 29 | pages = 14178–14189 | date = October 1987 | pmid = 3308887 | doi = 10.1016/S0021-9258(18)47921-5 | doi-access = free }}</ref> This process of promoter location has been attributed to the structure of the holoenzyme to DNA and sigma 4 to DNA complexes.<ref>{{cite journal | vauthors = Borukhov S, Nudler E | title = RNA polymerase holoenzyme: structure, function and biological implications | journal = Current Opinion in Microbiology | volume = 6 | issue = 2 | pages = 93–100 | date = April 2003 | pmid = 12732296 | doi = 10.1016/s1369-5274(03)00036-5 }}</ref>

== Diseases associated with aberrant function ==

Most diseases are heterogeneous in cause, meaning that one "disease" is often many different diseases at the molecular level, though symptoms exhibited and response to treatment may be identical.  How diseases of different molecular origin respond to treatments is partially addressed in the discipline of [[pharmacogenomics]].

Not listed here are the many kinds of cancers involving aberrant transcriptional regulation owing to creation of [[chimeric gene]]s through pathological [[chromosomal translocation]]. Importantly, intervention in the number or structure of promoter-bound proteins is one key to treating a disease without affecting expression of unrelated genes sharing elements with the target gene.<ref>{{cite journal | vauthors = Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA | display-authors = 6 | title = Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? | journal = BioEssays | volume = 31 | issue = 6 | pages = 629–641 | date = June 2009 | pmid = 19382224 | doi = 10.1002/bies.200800138 | s2cid = 205469320 }}</ref> Some genes whose change is not desirable are capable of influencing the potential of a cell to become cancerous.<ref>{{cite journal | vauthors = Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V | title = The role of ATF-2 in oncogenesis | journal = BioEssays | volume = 30 | issue = 4 | pages = 314–327 | date = April 2008 | pmid = 18348191 | doi = 10.1002/bies.20734 | s2cid = 678541 }}</ref>

==CpG islands in promoters==
{{main|Regulation of transcription in cancer}}

In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a [[CpG site#CpG islands|CpG island]].<ref name="pmid16432200">{{cite journal | vauthors = Saxonov S, Berg P, Brutlag DL | title = A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 5 | pages = 1412–1417 | date = January 2006 | pmid = 16432200 | pmc = 1345710 | doi = 10.1073/pnas.0510310103 | doi-access = free | bibcode = 2006PNAS..103.1412S }}</ref><ref name="pmid21576262">{{cite journal | vauthors = Deaton AM, Bird A | title = CpG islands and the regulation of transcription | journal = Genes & Development | volume = 25 | issue = 10 | pages = 1010–1022 | date = May 2011 | pmid = 21576262 | pmc = 3093116 | doi = 10.1101/gad.2037511 }}</ref>   CpG islands are generally 200 to 2000 base pairs long, have a C:G [[base pair]] content >50%, and have regions of [[DNA]] where a [[cytosine]] [[nucleotide]] is followed by a [[guanine]] nucleotide and this occurs frequently in the linear [[DNA sequence|sequence]] of [[Base pair|base]]s along its [[Directionality (molecular biology)|5' → 3' direction]].

Distal promoters also frequently contain CpG islands, such as the promoter of the DNA repair gene ''[[ERCC1]]'', where the CpG island-containing promoter is located about 5,400 nucleotides upstream of the coding region of the ''ERCC1'' gene.<ref name="pmid19626585">{{cite journal | vauthors = Chen HY, Shao CJ, Chen FR, Kwan AL, Chen ZP | title = Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas | journal = International Journal of Cancer | volume = 126 | issue = 8 | pages = 1944–1954 | date = April 2010 | pmid = 19626585 | doi = 10.1002/ijc.24772 | doi-access = free }}</ref>  CpG islands also occur frequently in promoters for [[Noncoding DNA#Noncoding functional RNA|functional noncoding RNAs]] such as [[microRNA]]s.

===Methylation of CpG islands stably silences genes===

In humans, DNA methylation occurs at the 5' position of the pyrimidine ring of the cytosine residues within [[CpG site]]s to form [[5-methylcytosine]]s.  The presence of multiple methylated CpG sites in CpG islands of promoters causes stable silencing of genes.<ref name=Bird />  Silencing of a gene may be initiated by other mechanisms, but this is often followed by methylation of CpG sites in the promoter CpG island to cause the stable silencing of the gene.<ref name=Bird />

===Promoter CpG hyper/hypo-methylation in cancer===

Generally, in progression to cancer, hundreds of genes are [[Regulation of transcription in cancer#Transcription silencing/activation in cancers|silenced or activated]].  Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation (see [[DNA methylation in cancer]]).  DNA methylation causing silencing in cancer typically occurs at multiple [[CpG site]]s in the [[CpG site#CpG island|CpG island]]s that are present in the promoters of protein coding genes.

Altered expressions of [[microRNA]]s also silence or activate many genes in progression to cancer (see [[MicroRNA#cancer|microRNAs in cancer]]).  Altered microRNA expression occurs through [[Regulation of transcription in cancer#Transcription silencing/activation in cancers|hyper/hypo-methylation]] of [[CpG site]]s in [[CpG site#CpG island|CpG island]]s in promoters controlling transcription of the [[microRNA]]s.

Silencing of DNA repair genes through methylation of CpG islands in their promoters appears to be especially important in progression to cancer (see [[DNA methylation in cancer#Likely role of hypermethylation of DNA repair genes in cancer|methylation of DNA repair genes in cancer]]).

==Canonical sequences and wild-type==
The usage of the term [[canonical sequence]] to refer to a promoter is often problematic, and can lead to misunderstandings about promoter sequences. Canonical implies perfect, in some sense.

In the case of a transcription factor binding site, there may be a single sequence that binds the protein most strongly under specified cellular conditions. This might be called canonical.

However, natural selection may favor less energetic binding as a way of regulating transcriptional output. In this case, we may call the most common sequence in a population the wild-type sequence. It may not even be the most advantageous sequence to have under prevailing conditions.

Recent evidence also indicates that several genes (including the [[proto-oncogene]] [[c-myc]]) have [[G-quadruplex]] motifs as potential regulatory signals.

== Synthetic promoter design and engineering ==
Promoters are important gene regulatory elements used in tuning [[Synthetic biology|synthetically designed]] genetic circuits and [[metabolic network]]s. For example, to overexpress an important gene in a network, to yield higher production of target protein, synthetic biologists design promoters to upregulate its [[Transcription (biology)|expression]]. Automated [[algorithm]]s can be used to design neutral DNA or insulators that do not trigger gene expression of downstream sequences.<ref>{{cite journal | vauthors = Hossain A, Lopez E, Halper SM, Cetnar DP, Reis AC, Strickland D, Klavins E, Salis HM | display-authors = 6 | title = Automated design of thousands of nonrepetitive parts for engineering stable genetic systems | journal = Nature Biotechnology | volume = 38 | issue = 12 | pages = 1466–1475 | date = December 2020 | pmid = 32661437 | doi = 10.1038/s41587-020-0584-2 | s2cid = 220506228 | url = https://scholarsphere.psu.edu/resources/bc01023b-9262-4356-9e2a-81eb4d8e0068 }}</ref><ref name=":0" />

==Diseases that may be associated with variations==
Some cases of many genetic diseases are associated with variations in promoters or transcription factors.

Examples include:
* [[Asthma]]<ref>{{cite journal | vauthors = Hobbs K, Negri J, Klinnert M, Rosenwasser LJ, Borish L | title = Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma | journal = American Journal of Respiratory and Critical Care Medicine | volume = 158 | issue = 6 | pages = 1958–1962 | date = December 1998 | pmid = 9847292 | doi = 10.1164/ajrccm.158.6.9804011 }}</ref><ref>{{cite journal | vauthors = Burchard EG, Silverman EK, Rosenwasser LJ, Borish L, Yandava C, Pillari A, Weiss ST, Hasday J, Lilly CM, Ford JG, Drazen JM | display-authors = 6 | title = Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma | journal = American Journal of Respiratory and Critical Care Medicine | volume = 160 | issue = 3 | pages = 919–922 | date = September 1999 | pmid = 10471619 | doi = 10.1164/ajrccm.160.3.9812024 }}</ref>
* [[Beta thalassemia]]<ref>{{cite journal | vauthors = Kulozik AE, Bellan-Koch A, Bail S, Kohne E, Kleihauer E | title = Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element | journal = Blood | volume = 77 | issue = 9 | pages = 2054–2058 | date = May 1991 | pmid = 2018842 | doi = 10.1182/blood.V77.9.2054.2054 | doi-access = free }}</ref>
* [[Rubinstein-Taybi syndrome]]<ref>{{cite journal | vauthors = Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ | display-authors = 6 | title = Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP | journal = Nature | volume = 376 | issue = 6538 | pages = 348–351 | date = July 1995 | pmid = 7630403 | doi = 10.1038/376348a0 | s2cid = 4254507 | bibcode = 1995Natur.376..348P }}</ref>

== Constitutive vs regulated ==
Some promoters are called constitutive as they are active in all circumstances in the cell, while others are [[Regulation of gene expression|regulated]], becoming active in the cell only in response to specific stimuli.

== Tissue-specific promoter ==
A tissue-specific promoter is a promoter that has activity in only certain cell types.

== Use of the term ==
When referring to a promoter some authors actually mean promoter + [[Operator (biology)|operator]]; i.e., the lac promoter is IPTG inducible, meaning that besides the lac promoter, the [[lac operon]] is also present. If the lac operator were not present the [[Isopropyl β-D-1-thiogalactopyranoside|IPTG]] would not have an inducible effect.{{cn|date=October 2022}}
Another example is the [[Tac-Promoter]] system (Ptac). Notice how tac is written as a tac promoter, while in fact tac is actually both a promoter and an operator.<ref>{{cite web | vauthors =  Maloy S |url=http://www.sci.sdsu.edu/~smaloy/MicrobialGenetics/topics/in-vitro-genetics/expression-vectors.html|title=Expression vectors| work = San Diego State University }}</ref>

== See also ==
{{div col|colwidth=30em}}
* [[Activator (genetics)]]
* [[Enhancer (genetics)]]
* [[Glossary of gene expression terms]]
* [[Operon]]
* [[Regulation of gene expression]]
* [[Repressor]]
* [[Transcription factor]]
* [[Promoter bashing]]
{{Div col end}}

== References ==
{{Reflist}}

== External links ==
{{Commons category|Genetic promoter regions}}
* [http://www.oreganno.org ORegAnno – Open Regulatory Annotation Database]
* [https://www.youtube.com/watch?v=A26YxzuLYgs Identifying a Protein Binding Sites on DNA molecule ] YouTube tutorial video
* [https://web.archive.org/web/20070502172603/http://www.pleiades.org/ Pleiades Promoter Project] – a research project with an aim to generate 160 fully characterized, human DNA promoters of less than 4 kb (MiniPromoters) to drive [[gene expression]] in defined brain regions of therapeutic interests.
* [http://www.nature.com/encode/#/threads/rna-and-chromatin-modification-patterns-around-promoters ENCODE threads Explorer] RNA and chromatin modification patterns around promoters. [[Nature (journal)]]

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{{Gene expression}}
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[[Category:Gene expression]]