Cis-regulatory element

cis-Regulatory Elements (CREs) are regions of non-coding DNA which regulate the transcription of nearby genes. The Latin prefix cis translates to “on this side”. CREs are found in the vicinity of the gene, or genes, they regulate. CREs typically regulate gene transcription by functioning as binding sites for transcription factors.

1 Overview
2 Promoters
3 Evolutionary Role of CREs
4 Examples of CREs
- 4.1 Examples of cis-regulatory elements in RNA
5 See also
6 References
7 Further reading
8 References

Overview

The 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 (Ayoubi, 1996; Butler, 2002). This regulatory region includes the site where transcription is initiated and the region approximately 35 bp upstream or downstream from the initiation site (Butler, 2002). Promoters usually have the following four components: the TATA box, a TFIIB recognition site, an initiator, and the downstream core promoter element (Butler, 2002). Interestingly, it has been found that a single gene can contain multiple promoter sites (Ayoubi, 1996). 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 (Butler, 2002). 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 (Wittkopp, 2012).

Evolutionary Role of CREs

CREs have an important evolutionary role. The coding regions of genes are often well polymorphisms occurring within non-coding sequences have a profound effect on phenotype by altering gene expression (Wittkopp, 2012). 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 of CREs

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. This term 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 of cis-regulatory elements in RNA

RNA elements
Type	Abbr.	Function	Distribution	Ref.
Frameshift element		Regulates alternative frame use with messenger RNAs	Archaea, Bacteria, Eukaryota, RNA viruses	^[1]^[2]^[3]
Internal ribosome entry site	IRES	Initiates translation in the middle of a messenger RNA	RNA virus, Eukaryota	^[4]
Iron response element	IRE	Regulates the expression of iron associated genes	Eukaryota	^[5]
Leader peptide		Regulates transcription of associated genes and/or operons	Bacteria	^[6]
Pyrrolysine insertion sequence	PYLIS	directs the cell to translate immediately adjacent UAG stop codons into pyrrolysine	Archaea	^[7]
Riboswitch		Gene regulation	Bacteria, Eukaryota	^[8]
RNA thermometer		Gene regulation	Bacteria	^[9]
Selenocysteine insertion sequence	SECIS	directs the cell to translate UGA stop-codons as selenocysteines	Metazoa	^[10]

References

Van De Ven, W. (1996). "Regulation of gene expression by alternative promoters". The FASEB Journal 10 (4): 453–460.
Butler, J., Kadonaga, J. (2002). "The RNA Polymerase II core promoter: a key component to the regulation of gene expression". Genes & Development 16 (20): 2583–2592.

Wittkopp, P., Kalay, G. "Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence". Nature Review Genetics 13: 59–69.

References

^ 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.

^ Chung BY, Firth AE, Atkins JF (2010). "Frameshifting in alphaviruses: a diversity of 3' stimulatory structures.". J Mol Biol 397 (2): 448–56.

^ Giedroc DP, Cornish PV (2009). "Frameshifting RNA pseudoknots: structure and mechanism.". Virus Res 139 (2): 193–208.

^ 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.

^ 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.

^ Platt T (1986). "Transcription termination and the regulation of gene expression.". Annu Rev Biochem 55: 339–72.

^ 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.

^ Breaker RR (2008). "Complex riboswitches". Science 319 (5871): 1795–7.

^ Kortmann, J; Narberhaus, F (Mar 16, 2012). "Bacterial RNA thermometers: molecular zippers and switches.". Nature reviews. Microbiology 10 (4): 255–65.

^ 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.

Cis-regulatory element