Regulator gene

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Gene regulatory pathway Gene Regulatory Network.jpg
Gene regulatory pathway

In genetics, a regulator gene, regulator, or regulatory gene is a gene involved in controlling the expression of one or more other genes. Regulatory sequences, which encode regulatory genes, are often at the five prime end (5') to the start site of transcription of the gene they regulate. In addition, these sequences can also be found at the three prime end (3') to the transcription start site. In both cases, whether the regulatory sequence occurs before (5') or after (3') the gene it regulates, the sequence is often many kilobases away from the transcription start site. A regulator gene may encode a protein, or it may work at the level of RNA, as in the case of genes encoding microRNAs. An example of a regulator gene is a gene that codes for a repressor protein that inhibits the activity of an operator (a gene which binds repressor proteins thus inhibiting the translation of RNA to protein via RNA polymerase). [1]

Contents

In prokaryotes, regulator genes often code for repressor proteins. Repressor proteins bind to operators or promoters, preventing RNA polymerase from transcribing RNA. They are usually constantly expressed so the cell always has a supply of repressor molecules on hand. [2] Inducers cause repressor proteins to change shape or otherwise become unable to bind DNA, allowing RNA polymerase to continue transcription. Regulator genes can be located within an operon, adjacent to it, or far away from it. [3]

Other regulatory genes code for activator proteins. An activator binds to a site on the DNA molecule and causes an increase in transcription of a nearby gene. In prokaryotes, a well-known activator protein is the catabolite activator protein (CAP), involved in positive control of the lac operon.

In the regulation of gene expression, studied in evolutionary developmental biology (evo-devo), both activators and repressors play important roles. [4]

Regulatory genes can also be described as positive or negative regulators, based on the environmental conditions that surround the cell. Positive regulators are regulatory elements that permit RNA polymerase binding to the promoter region, thus allowing transcription to occur. In terms of the lac operon, the positive regulator would be the CRP-cAMP complex that must be bound close to the site of the start of transcription of the lac genes. The binding of this positive regulator allows RNA polymerase to bind successfully to the promoter of the lac gene sequence which advances the transcription of lac genes; lac Z, lac Y, and lac A. Negative regulators are regulatory elements which obstruct the binding of RNA polymerase to the promoter region, thus repressing transcription. In terms of the lac operon, the negative regulator would be the lac repressor which binds to the promoter in the same site that RNA polymerase normally binds. The binding of the lac repressor to RNA polymerase's binding site inhibits the transcription of the lac genes. Only when a corepressor is bound to the lac repressor will the binding site be free for RNA polymerase to carry out transcription of the lac genes. [5] [6] [7]

Gene regulatory elements

Promoters reside at the beginning of the gene and serve as the site where the transcription machinery assembles and transcription of the gene begins. Enhancers turn on the promoters at specific locations, times, and levels and can be simply defined as the “promoters of the promoter.” Silencers are thought to turn off gene expression at specific time points and locations. Insulators, also called boundary elements, are DNA sequences that create cis-regulatory boundaries that prevent the regulatory elements of one gene from affecting neighboring genes. The general dogma is that these regulatory elements get activated by the binding of transcription factors, proteins that bind to specific DNA sequences, and control mRNA transcription. There could be several transcription factors that need to bind to one regulatory element in order to activate it. In addition, several other proteins, called transcription cofactors, bind to the transcription factors themselves to control transcription. [8] [9]

Negative regulators

Negative regulators act to prevent transcription or translation. Examples such as cFLIP suppress cell death mechanisms leading to pathological disorders like cancer, and thus play a crucial role in drug resistance. Circumvention of such actors is a challenge in cancer therapy. [10] Negative regulators of cell death in cancer include cFLIP, Bcl2 family, Survivin, HSP, IAP, NF-κB, Akt, mTOR, and FADD. [10]

Detection

There are several different techniques to detect regulatory genes, but of the many there are a certain few that are used more frequently than others. One of these select few is called ChIP-chip. ChIP-chip is an in vivo technique used to determine genomic binding sites for transcription factors in two component system response regulators. In vitro microarray based assay (DAP-chip) can be used to determine gene targets and functions of two component signal transduction systems. This assay takes advantage of the fact that response regulators can be phosphorylated and thus activated in vitro using small molecule donors like acetyl phosphate. [11] [12]

Phylogenetic footprinting

Phylogenetic footprinting is a technique that utilizes multiple sequence alignments to determine locations of conserved sequences such as regulatory elements. Along with multiple sequence alignments, phylogenetic footprinting also requires statistical rates of conserved and non-conserved sequences. Using the information provided by multiple sequence alignments and statistical rates, one can identify the best conserved motifs in the orthologous regions of interest. [13] [14]

Related Research Articles

<span class="mw-page-title-main">Lambda phage</span> Bacteriophage that infects Escherichia coli

Enterobacteria phage λ is a bacterial virus, or bacteriophage, that infects the bacterial species Escherichia coli. It was discovered by Esther Lederberg in 1950. The wild type of this virus has a temperate life cycle that allows it to either reside within the genome of its host through lysogeny or enter into a lytic phase, during which it kills and lyses the cell to produce offspring. Lambda strains, mutated at specific sites, are unable to lysogenize cells; instead, they grow and enter the lytic cycle after superinfecting an already lysogenized cell.

<span class="mw-page-title-main">Promoter (genetics)</span> Region of DNA encouraging transcription

In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of itself, such as tRNA or rRNA. Promoters are located near the transcription start sites of genes, upstream on the DNA . Promoters can be about 100–1000 base pairs long, the sequence of which is highly dependent on the gene and product of transcription, type or class of RNA polymerase recruited to the site, and species of organism.

In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splicing to create monocistronic mRNAs that are translated separately, i.e. several strands of mRNA that each encode a single gene product. The result of this is that the genes contained in the operon are either expressed together or not at all. Several genes must be co-transcribed to define an operon.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

<span class="mw-page-title-main">Lac repressor</span> DNA-binding protein

The lac repressor (LacI) is a DNA-binding protein that inhibits the expression of genes coding for proteins involved in the metabolism of lactose in bacteria. These genes are repressed when lactose is not available to the cell, ensuring that the bacterium only invests energy in the production of machinery necessary for uptake and utilization of lactose when lactose is present. When lactose becomes available, it is firstly converted into allolactose by β-Galactosidase (lacZ) in bacteria. The DNA binding ability of lac repressor bound with allolactose is inhibited due to allosteric regulation, thereby genes coding for proteins involved in lactose uptake and utilization can be expressed.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<i>lac</i> operon Set genes encoding proteins and enzymes for lactose metabolism

The lactose operon is an operon required for the transport and metabolism of lactose in E. coli and many other enteric bacteria. Although glucose is the preferred carbon source for most enteric bacteria, the lac operon allows for the effective digestion of lactose when glucose is not available through the activity of beta-galactosidase. Gene regulation of the lac operon was the first genetic regulatory mechanism to be understood clearly, so it has become a foremost example of prokaryotic gene regulation. It is often discussed in introductory molecular and cellular biology classes for this reason. This lactose metabolism system was used by François Jacob and Jacques Monod to determine how a biological cell knows which enzyme to synthesize. Their work on the lac operon won them the Nobel Prize in Physiology in 1965.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

A transcriptional activator is a protein that increases transcription of a gene or set of genes. Activators are considered to have positive control over gene expression, as they function to promote gene transcription and, in some cases, are required for the transcription of genes to occur. Most activators are DNA-binding proteins that bind to enhancers or promoter-proximal elements. The DNA site bound by the activator is referred to as an "activator-binding site". The part of the activator that makes protein–protein interactions with the general transcription machinery is referred to as an "activating region" or "activation domain".

<span class="mw-page-title-main">Repressor</span> Sort of RNA-binding protein in molecular genetics

In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes into messenger RNA. An RNA-binding repressor binds to the mRNA and prevents translation of the mRNA into protein. This blocking or reducing of expression is called repression.

<span class="mw-page-title-main">Silencer (genetics)</span> Type of DNA sequence

In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.

In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely:

Cis-regulatory elements (CREs) or Cis-regulatory modules (CRMs) 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.

Gene structure is the organisation of specialised sequence elements within a gene. Genes contain most of the information necessary for living cells to survive and reproduce. In most organisms, genes are made of DNA, where the particular DNA sequence determines the function of the gene. A gene is transcribed (copied) from DNA into RNA, which can either be non-coding (ncRNA) with a direct function, or an intermediate messenger (mRNA) that is then translated into protein. Each of these steps is controlled by specific sequence elements, or regions, within the gene. Every gene, therefore, requires multiple sequence elements to be functional. This includes the sequence that actually encodes the functional protein or ncRNA, as well as multiple regulatory sequence regions. These regions may be as short as a few base pairs, up to many thousands of base pairs long.

<i>trp</i> operon Operon that codes for the components for production of tryptophan

The trp operon is a group of genes that are transcribed together, encoding the enzymes that produce the amino acid tryptophan in bacteria. The trp operon was first characterized in Escherichia coli, and it has since been discovered in many other bacteria. The operon is regulated so that, when tryptophan is present in the environment, the genes for tryptophan synthesis are repressed.

The L-arabinose operon, also called the ara or araBAD operon, is an operon required for the breakdown of the five-carbon sugar L-arabinose in Escherichia coli. The L-arabinose operon contains three structural genes: araB, araA, araD, which encode for three metabolic enzymes that are required for the metabolism of L-arabinose. AraB (ribulokinase), AraA, and AraD produced by these genes catalyse conversion of L-arabinose to an intermediate of the pentose phosphate pathway, D-xylulose-5-phosphate.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

The gal operon is a prokaryotic operon, which encodes enzymes necessary for galactose metabolism. Repression of gene expression for this operon works via binding of repressor molecules to two operators. These repressors dimerize, creating a loop in the DNA. The loop as well as hindrance from the external operator prevent RNA polymerase from binding to the promoter, and thus prevent transcription. Additionally, since the metabolism of galactose in the cell is involved in both anabolic and catabolic pathways, a novel regulatory system using two promoters for differential repression has been identified and characterized within the context of the gal operon.

RegulonDB is a database of the regulatory network of gene expression in Escherichia coli K-12. RegulonDB also models the organization of the genes in transcription units, operons and regulons. A total of 120 sRNAs with 231 total interactions which all together regulate 192 genes are also included. RegulonDB was founded in 1998 and also contributes data to the EcoCyc database.

The lacUV5 promoter is a mutated promoter from the Escherichia coli lac operon which is used in molecular biology to drive gene expression on a plasmid. lacUV5 is very similar to the classical lac promoter, containing just 2 base pair mutations in the -10 hexamer region, compared to the lac promoter. LacUV5 is among the most commonly used promoters in molecular biology because it requires no additional activators and it drives high levels of gene expression.

References

  1. ↑ "Regulatory gene - Biology-Online Dictionary". www.biology-online.org. Retrieved 2016-02-06.
  2. ↑ Campbell Biology—Concepts and Connections 7th Edition. Pearson Education. 2009. pp. 210–211.
  3. ↑ Mayer, Gene. "BACTERIOLOGY - CHAPTER NINE GENETIC REGULATORY MECHANISMS". Microbiology and Immunology Online. University of South Carolina School of Medicine. Retrieved 30 December 2012.
  4. ↑ Suzuki, David (2005). Introduction to Genetic Analysis. San Francisco: W.H. Freeman. ISBN   978-0-7167-4939-4.
  5. ↑ Casadaban, Malcolm J. (1976-07-05). "Regulation of the regulatory gene for the arabinose pathway, araC". Journal of Molecular Biology. 104 (3): 557–566. doi:10.1016/0022-2836(76)90120-0. PMID   781294.
  6. ↑ Wong, Oi Kwan; Guthold, Martin; Erie, Dorothy A; Gelles, Jeff (2008). "Interconvertible Lac Repressor–DNA Loops Revealed by Single-Molecule Experiments". PLOS Biology. 6 (9): e232. doi: 10.1371/journal.pbio.0060232 . PMC   2553838 . PMID   18828671.
  7. ↑ Jiang, Xiaofeng; Pan, Hui; Nabhan, Joseph F.; Krishnan, Ramaswamy; Koziol-White, Cynthia; Panettieri, Reynold A.; Lu, Quan (2012-05-01). "A novel EST-derived RNAi screen reveals a critical role for farnesyl diphosphate synthase in β2-adrenergic receptor internalization and down-regulation". The FASEB Journal. 26 (5): 1995–2007. doi:10.1096/fj.11-193870. ISSN   0892-6638. PMC   3336790 . PMID   22278941.
  8. ↑ Khan, Arshad H.; Lin, Andy; Smith, Desmond J. (2012-09-24). "Discovery and Characterization of Human Exonic Transcriptional Regulatory Elements". PLOS ONE. 7 (9): e46098. Bibcode:2012PLoSO...746098K. doi: 10.1371/journal.pone.0046098 . ISSN   1932-6203. PMC   3454335 . PMID   23029400.
  9. ↑ Ahituv, Nadav (2012). Ahituv, Nadav (ed.). Gene Regulatory Elements. doi:10.1007/978-1-4614-1683-8. ISBN   978-1-4614-1682-1. S2CID   40483427.{{cite book}}: |journal= ignored (help)
  10. 1 2 Razaghi, Ali; Heimann, Kirsten; Schaeffer, Patrick M.; Gibson, Spencer B. (2018-01-10). "Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies". Apoptosis. 23 (2): 93–112. doi:10.1007/s10495-018-1440-4. ISSN   1360-8185. PMID   29322476. S2CID   3424489.
  11. ↑ Kogelman, Lisette J A; Cirera, Susanna; Zhernakova, Daria V; Fredholm, Merete; Franke, Lude; Kadarmideen, Haja N (2014-09-30). "Identification of co-expression gene networks, regulatory genes and pathways for obesity based on adipose tissue RNA Sequencing in a porcine model". BMC Medical Genomics. 7: 57. doi: 10.1186/1755-8794-7-57 . ISSN   1755-8794. PMC   4183073 . PMID   25270054.
  12. ↑ Rajeev, Lara; Luning, Eric G.; Mukhopadhyay, Aindrila (2014). "DNA-affinity-purified Chip (DAP-chip) Method to Determine Gene Targets for Bacterial Two component Regulatory Systems | Protocol". Journal of Visualized Experiments (89): e51715. doi:10.3791/51715. PMC   4233932 . PMID   25079303 . Retrieved 2016-04-08.
  13. ↑ Satija, Rahul; Novák, Ádám; Miklós, István; Lyngsø, Rune; Hein, Jotun (2009-08-28). "BigFoot: Bayesian alignment and phylogenetic footprinting with MCMC". BMC Evolutionary Biology. 9: 217. doi: 10.1186/1471-2148-9-217 . ISSN   1471-2148. PMC   2744684 . PMID   19715598.
  14. ↑ Blanchette, Mathieu; Tompa, Martin (2002-05-01). "Discovery of Regulatory Elements by a Computational Method for Phylogenetic Footprinting". Genome Research. 12 (5): 739–748. doi:10.1101/gr.6902. ISSN   1088-9051. PMC   186562 . PMID   11997340.
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