cis-regulatory element

cis-regulatory elements (CREs) are regions of non-coding DNA which regulate the transcription of nearby genes. CREs are vital components of genetic regulatory networks, which in turn control morphogenesis, the development of anatomy, and other aspects of developmental biology, now being unified in evo-devo.

CREs are found in the vicinity of the genes that they regulate. CREs typically regulate gene transcription by functioning as binding sites for transcription factors. A single transcription factor may bind to many CREs, and hence control the expression of many genes. The Latin prefix cis means "on this side", i.e. upstream of genes during transcription.

Overview

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

Promoters are relatively short sequences of DNA, approximately 40 base pairs (bp), usually located upstream of a transcription start site.^[1] This regulatory region includes the site where transcription is initiated and the region approximately 35 bp upstream or downstream from the initiation site.^[1] In eukaryotes, promoters usually have the following four components: the TATA box, a TFIIB recognition site, an initiator, and the downstream core promoter element.^[1] It has been found that a single gene can contain multiple promoter sites.^[2] 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.^[1] 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. Contrastingly, enhancers influence 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.^[3]

Evolutionary role

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.^[3] 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.

Examples

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".

There are cis-regulatory and trans-regulatory elements. Cis-regulatory elements are often binding sites for one or more trans-acting factors.

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

RNA elements
Type	Abbr.	Function	Distribution	Ref.
Frameshift element		Regulates alternative frame use with messenger RNAs	Archaea, bacteria, Eukaryota, RNA viruses	^[4]^[5]^[6]
Internal ribosome entry site	IRES	Initiates translation in the middle of a messenger RNA	RNA virus, Eukaryota	^[7]
Iron response element	IRE	Regulates the expression of iron associated genes	Eukaryota	^[8]
Leader peptide		Regulates transcription of associated genes and/or operons	Bacteria	^[9]
Pyrrolysine insertion sequence	PYLIS	Directs the cell to translate immediately adjacent UAG stop codons into pyrrolysine	Archaea	^[10]
Riboswitch		Gene regulation	Bacteria, Eukaryota	^[11]
RNA thermometer		Gene regulation	Bacteria	^[12]
Selenocysteine insertion sequence	SECIS	Directs the cell to translate UGA stop-codons as selenocysteines	Metazoa	^[13]

References

1 2 3 4 Butler, J. E.F. (2002). "The RNA polymerase II core promoter: a key component in the regulation of gene expression". Genes & Development 16 (20): 2583–2592. doi:10.1101/gad.1026202. ISSN 0890-9369. PMID 12381658.
↑ Sangdun Choi (17 May 2008). Introduction to Systems Biology. Springer Science & Business Media. p. 78. ISBN 978-1-59745-531-2.
1 2 Wittkopp, Patricia J.; Kalay, Gizem (2011). "Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence". Nature Reviews Genetics. doi:10.1038/nrg3095. ISSN 1471-0056.
↑ Bekaert M, Firth AE, Zhang Y, Gladyshev VN, Atkins JF, Baranov PV (2010). "Recode-2: new design, new search tools, and many more genes.". Nucleic Acids Res 38 (Database issue): D69–74. doi:10.1093/nar/gkp788. PMC 2808893. PMID 19783826.
↑ Chung BY, Firth AE, Atkins JF (2010). "Frameshifting in alphaviruses: a diversity of 3' stimulatory structures.". J Mol Biol 397 (2): 448–56. doi:10.1016/j.jmb.2010.01.044. PMID 20114053.
↑ Giedroc DP, Cornish PV (2009). "Frameshifting RNA pseudoknots: structure and mechanism.". Virus Res 139 (2): 193–208. doi:10.1016/j.virusres.2008.06.008. PMC 2670756. PMID 18621088.
↑ Mokrejs M, Vopálenský V, Kolenaty O; et al. (January 2006). "IRESite: the database of experimentally verified IRES structures (www.iresite.org)". Nucleic Acids Res. 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". Proc. Natl. Acad. Sci. U.S.A. 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.". Annu Rev Biochem 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 (2008). "Complex riboswitches". Science 319 (5871): 1795–7. doi:10.1126/science.1152621. PMID 18369140.
↑ Kortmann, J; Narberhaus, F (Mar 16, 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 (1996). "A novel RNA structural motif in the selenocysteine insertion element of eukaryotic selenoprotein mRNAs". RNA 2 (4): 367–379. PMC 1369379. PMID 8634917.