Cis-regulatory elements (CREs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphogenesis, the development of anatomy, and other aspects of embryonic development, studied in evolutionary developmental biology.
CREs are found in the vicinity of the genes that they regulate. CREs typically regulate gene transcription by binding to transcription factors. A single transcription factor may bind to many CREs, and hence control the expression of many genes (pleiotropy). The Latin prefix cis means "on this side", i.e. on the same molecule of DNA as the gene(s) to be transcribed. CREs are often but not always upstream of the transcription site.
CREs contrast with trans-regulatory elements (TREs). TREs code for transcription factors.
The genome of an organism contains anywhere from a few hundred to thousands of different genes, all encoding a singular product or more. For numerous reasons, including organizational maintenance, energy conservation, and generating phenotypic variance, it is important that genes are only expressed when they are needed. The most efficient way for an organism to regulate genetic expression is at the transcriptional level. CREs function to control transcription by acting nearby or within a gene. The most well characterized types of CREs are enhancers and promoters. Both of these sequence elements are structural regions of DNA that serve as transcriptional regulators.
Promoters are CREs consisting of relatively short sequences of DNA which include the site where transcription is initiated and the region approximately 35 bp upstream or downstream from the initiation site (bp). In eukaryotes, promoters usually have the following four components: the TATA box, a TFIIB recognition site, an initiator, and the downstream core promoter element. It has been found that a single gene can contain multiple promoter sites. In order to initiate transcription of the downstream gene, a host of DNA-binding proteins called transcription factors (TFs) must bind sequentially to this region. Only once this region has been bound with the appropriate set of TFs, and in the proper order, can RNA polymerase bind and begin transcribing the gene.
Enhancers are CREs that influence (enhance) the transcription of genes on the same molecule of DNA and can be found upstream, downstream, within the introns, or even relatively far away from the gene they regulate. Multiple enhancers can act in a coordinated fashion to regulate transcription of one gene.
Silencers are CREs that can bind transcription regulation factors (proteins) called repressors, thereby preventing transcription of a gene. The term "silencer" can also refer to a region in the 3' untranslated region of messenger RNA, that bind proteins which suppress translation of that mRNA molecule, but this usage is distinct from its use in describing a CRE.
CREs have an important evolutionary role. The coding regions of genes are often well conserved among organisms; yet different organisms display marked phenotypic diversity. It has been found that polymorphisms occurring within non-coding sequences have a profound effect on phenotype by altering gene expression. Mutations arising within a CRE can generate expression variance by changing the way TFs bind. Tighter or looser binding of regulatory proteins will lead to up- or down-regulated transcription.
An example of a cis-acting regulatory sequence is the operator in the lac operon. This DNA sequence is bound by the lac repressor, which, in turn, prevents transcription of the adjacent genes on the same DNA molecule. The lac operator is, thus, considered to "act in cis" on the regulation of the nearby genes. The operator itself does not code for any protein or RNA.
In contrast, trans-regulatory elements are diffusible factors, usually proteins, that may modify the expression of genes distant from the gene that was originally transcribed to create them. For example, a transcription factor that regulates a gene on chromosome 6 might itself have been transcribed from a gene on chromosome 11. The term trans-regulatory is constructed from the Latin root trans, which means "across from".
To summarize, cis-regulatory elements are present on the same molecule of DNA as the gene they regulate whereas trans-regulatory elements can regulate genes distant from the gene from which they were transcribed.
Examples in RNA
|Frameshift element||Regulates alternative frame use with messenger RNAs||Archaea, bacteria, Eukaryota, RNA viruses|||
|Internal ribosome entry site||IRES||Initiates translation in the middle of a messenger RNA||RNA virus, Eukaryota|||
|Iron response element||IRE||Regulates the expression of iron associated genes||Eukaryota|||
|Leader peptide||Regulates transcription of associated genes and/or operons||Bacteria|||
|Pyrrolysine insertion sequence||PYLIS||Directs the cell to translate immediately adjacent UAG stop codons into pyrrolysine||Archaea|||
|Riboswitch||Gene regulation||Bacteria, Eukaryota|||
|RNA thermometer||Gene regulation||Bacteria|||
|Selenocysteine insertion sequence||SECIS||Directs the cell to translate UGA stop-codons as selenocysteines||Metazoa|||
- Butler JE, Kadonaga JT (October 2002). "The RNA polymerase II core promoter: a key component in the regulation of gene expression". Genes & Development. 16 (20): 2583–92. doi:10.1101/gad.1026202. PMID 12381658.
- Choi S (17 May 2008). Introduction to Systems Biology. Springer Science & Business Media. p. 78. ISBN 978-1-59745-531-2.
- Wittkopp PJ, Kalay G (December 2011). "Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence". Nature Reviews. Genetics. 13 (1): 59–69. doi:10.1038/nrg3095. PMID 22143240.
- Bekaert M, Firth AE, Zhang Y, Gladyshev VN, Atkins JF, Baranov PV (January 2010). "Recode-2: new design, new search tools, and many more genes". Nucleic Acids Research. 38 (Database issue): D69–74. doi:10.1093/nar/gkp788. PMC 2808893. PMID 19783826.
- Chung BY, Firth AE, Atkins JF (March 2010). "Frameshifting in alphaviruses: a diversity of 3' stimulatory structures". Journal of Molecular Biology. 397 (2): 448–56. doi:10.1016/j.jmb.2010.01.044. PMID 20114053.
- Giedroc DP, Cornish PV (February 2009). "Frameshifting RNA pseudoknots: structure and mechanism". Virus Research. 139 (2): 193–208. doi:10.1016/j.virusres.2008.06.008. PMC 2670756. PMID 18621088.
- Mokrejs M, Vopálenský V, Kolenaty O, Masek T, Feketová Z, Sekyrová P, Skaloudová B, Kríz V, Pospísek M (January 2006). "IRESite: the database of experimentally verified IRES structures (www.iresite.org)". Nucleic Acids Research. 34 (Database issue): D125–30. doi:10.1093/nar/gkj081. PMC 1347444. PMID 16381829.
- Hentze MW, Kühn LC (August 1996). "Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8175–82. doi:10.1073/pnas.93.16.8175. PMC 38642. PMID 8710843.
- Platt T (1986). "Transcription termination and the regulation of gene expression". Annual Review of Biochemistry. 55: 339–72. doi:10.1146/annurev.bi.55.070186.002011. PMID 3527045.
- Théobald-Dietrich A, Giegé R, Rudinger-Thirion J (2005). "Evidence for the existence in mRNAs of a hairpin element responsible for ribosome dependent pyrrolysine insertion into proteins". Biochimie. 87 (9–10): 813–7. doi:10.1016/j.biochi.2005.03.006. PMID 16164991.
- Breaker RR (March 2008). "Complex riboswitches". Science. 319 (5871): 1795–7. doi:10.1126/science.1152621. PMID 18369140.
- Kortmann J, Narberhaus F (March 2012). "Bacterial RNA thermometers: molecular zippers and switches". Nature Reviews. Microbiology. 10 (4): 255–65. doi:10.1038/nrmicro2730. PMID 22421878.
- Walczak R, Westhof E, Carbon P, Krol A (April 1996). "A novel RNA structural motif in the selenocysteine insertion element of eukaryotic selenoprotein mRNAs". RNA. 2 (4): 367–79. PMC 1369379. PMID 8634917.
- Wray GA (March 2007). "The evolutionary significance of cis-regulatory mutations". Nature Reviews. Genetics. 8 (3): 206–16. doi:10.1038/nrg2063. PMID 17304246.
- Gompel N, Prud'homme B, Wittkopp PJ, Kassner VA, Carroll SB (February 2005). "Chance caught on the wing: cis-regulatory evolution and the origin of pigment patterns in Drosophila". Nature. 433 (7025): 481–7. doi:10.1038/nature03235. PMID 15690032.
- Prud'homme B, Gompel N, Rokas A, Kassner VA, Williams TM, Yeh SD, True JR, Carroll SB (April 2006). "Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene". Nature. 440 (7087): 1050–3. doi:10.1038/nature04597. PMID 16625197.
- Stern DL (August 2000). "Evolutionary developmental biology and the problem of variation". Evolution; International Journal of Organic Evolution. 54 (4): 1079–91. doi:10.1111/j.0014-3820.2000.tb00544.x. PMID 11005278.
- Weatherbee SD, Carroll SB, Grenier JK (2004). From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design. Cambridge, MA: Blackwell Publishers. ISBN 1-4051-1950-0.