Cis-regulatory element

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.

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 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).[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.

Enhancers

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.[3] A number of genome-wide sequencing projects have revealed that enhancers are often transcribed to long non-coding RNA (lncRNA) or enhancer RNA (eRNA), whose changes in levels frequently correlate with those of the target gene mRNA.[4]

Silencers

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 binds proteins which suppress translation of that mRNA molecule, but this usage is distinct from its use in describing a CRE.

Operators

Operators are CREs in prokaryotes and some eukaryotes that exist within operons, where they can bind proteins called repressors to affect transcription.

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	[5][6][7]
Internal ribosome entry site	IRES	Initiates translation in the middle of a messenger RNA	RNA virus, Eukaryota	[8]
Iron response element	IRE	Regulates the expression of iron associated genes	Eukaryota	[9]
Leader peptide		Regulates transcription of associated genes and/or operons	Bacteria	[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

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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): 8175–8182. doi:10.1073/pnas.93.16.8175. PMC 38642. PMID 8710843.
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