Editing Promoter (genetics) (section)

====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" />