Cis-regulatory module
Encyclopedia
Cis-regulatory module is a stretch of DNA
, usually 100-1000 DNA base pairs in length, where a number of transcription factor
s can bind and regulate expression
of nearby gene
s. One cis-regulatory element can regulate several genes, and conversely, one gene can have several cis-regulatory modules. Cis-regulatory modules are one of several types of functional regulatory elements. Regulatory elements are binding sites for transcription factors, which are involved in gene regulation. Cis-regulatory modules perform a large amount of developmental information processing. Cis-regulatory modules are non-random clusters at their specified target site that contain transcription factor binding sites. They are labeled as cis because they are typically located on the same DNA as the genes they control as opposed to trans
, which refers to effects on genes not located on the same strand or farther away, such as transcription factors. The original definition presented cis-regulatory modules as enhancers of cis-acting DNA, which increased the rate of transcription from a linked promoter. However, this definition has changed to define cis-regulatory modules as a DNA sequence with transcription factor binding sites which are clustered into modular structures, including -but not limited to- locus control regions, promoters, enhancers, silencers, boundary control elements and other modulators. Cis-regulatory modules can be divided into classes. Enhancers regulate gene expression positively. Insulators work indirectly by interacting with other nearby cis-regulatory modules. Silencer
s act by silencing genes. Cis-regulatory modules carry out their function by integrating the active transcription factors and the associated co-factors at a specific time and place in the cell, this information is read and an output is given.
s and epigenetic modification
s serve as inputs, and the output of the module is the command given to the transcription machinery, which in turn determines the rate of gene transcription or whether it is turned on or off. There are two types of transcription factor inputs: those that determine when the target gene is to be expressed and those that serve as functional drivers, which come into play only during specific situations during development. These inputs can come from different time points, can represent different signal ligands, or can come from different domains or lineages of cells. However, a lot still remains unknown. Additionally, the regulation of chromatin structure and nuclear organization also play a role in determining and controlling the function of cis-regulatory modules. Thus gene-regulation functions (GRF) provide a unique characteristic of a cis-regulatory module (CRM), relating the concentrations of transcription factors (input) to the promoter activities (output). The challenge is to predict GRFs. This challenge still remains unsolved. In general, gene-regulation functions do not use Boolean logic
, although in some cases the approximation of the Boolean logic
is still very useful.
1) The design of the cis-regulatory module determines the regulatory function.
2) In relation to development, these modules can generate both positive and negative outputs.
3) The output of each module is a product of the various operations performed on it. Common operations:
“OR” logic gate
- This design indicates that in an output will be given when either input is given [3].
“AND” logic gate– In this design two different regulatory factors are necessary to make sure that a positive output results.
“Toggle Switches”- This design occurs when the signal ligand is absent while the transcription factor is present; this transcription factor ends up acting as a dominant repressor. However, once the signal ligand is present the transcription factor’s role as repressor is eliminated and transcription can occur.
Other Boolean logic
operations can occur as well, such as sequence specific transcriptional repressors, which when they bind to the cis-regulatory module lead to an output of zero. Additionally, besides influence from the different logic operations, the output of a "cis"-regulatory module will also be influenced by prior events.
4) Cis-regulatory modules must interact with other regulatory elements. For the most part, even with the presence of functional overlap between cis-regulatory modules of a gene, the modules’ inputs and outputs tend to not be the same.
algorithms for predicting them. Most algorithms try to search for significant combinations of transcription factor binding sites (DNA binding site
s) in promoter sequences of co-expressed genes. More advanced methods combine the search for significant motifs with correlation in gene expression
datasets between transcription factors and target genes.
Both methods have been implemented, for example, in the ModuleMaster.
Other programs created for the identification and prediction of "cis-regulatory modules include:
Stubb uses hidden Markov model
s to identify statistically significant clusters of transcription factor combinations. It also uses a second related genome to improve the prediction accuracy of the model.
Bayesian Network
s use an algorithm that combines site predictions and tissue-specific expression data for transcription factors and target genes of interest. This model also uses regression trees to depict the relationship between the identified cis-regulatory module and the possible binding set of transcription factors.
CRÈME examine clusters of target sites for transcription factors of interest. This program uses a database of confirmed transcription factor binding sites that were annotated across the human genome
. A search algorithm
is applied to the data set to identify possible combinations of transcription factors, which have binding sites that are close to the promoter of the gene set of interest. The possible cis-regulatory modules are then statistically analyzed and the significant combinations are graphically represented
Active cis-regulatory modules in a genomic sequence have been difficult to identify. Problems in identification arise because often scientists find themselves with a small set of known transcription factors, so it makes it harder to identify statistically significant clusters of transcription factor binding sites. Additionally, high costs limit the use of large whole genome tiling array
s.
Highly cooperative and coordinated cis-regulatory modules are classified as enhanceosome
s. The architecture and the arrangement of the transcription factor binding sites are critical because disruption of the arrangement could cancel out the function.
Functional flexible cis-regulatory modules are called billboards. Their transcriptional output is the summation effect of the bound transcription factors.
Enhancers affect the probability of a gene being activated, but have little or no effect on rate.
Binary response model acts like an on/off switch for transcription. This model will increase or decrease the amount of cells that transcribe a gene, however it does not affect the rate of transcription.
Rheostatic response model describes cis-regulatory modules as regulators of the initiation rate of transcription of its associated gene.
DNA Scanning Model: In this model the transcription factor and cofactor
complex form at the cis-regulatory module and then continues to move along the DNA sequence until it finds the target gene promoter.
Looping Model: In this model the transcription factor binds to the cis-regulatory module, which then causes the looping of the DNA sequence and allows for the interaction with the target gene promoter.
Facilitated Tracking Model: This model combines parts of the two previous models. The transcription factor-cis-regulatory module complex causes the looping of the DNA sequence slowly towards the target promoter and forms a stable looped configuration.
depends on the architecture of the node
s, whose function is dependent on the multiple cis-regulatory modules. The layout of cis-regulatory modules can provide enough information to generate spatial and temporal patterns of gene expression. During development each domain, where each domain represents a different spatial regions of the embryo, of gene expression will be under the control of different cis-regulatory module(s). The design of regulatory modules help in producing feedback
, feed forward, and cross-regulatory loops.
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, usually 100-1000 DNA base pairs in length, where a number of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s can bind and regulate expression
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
of nearby gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s. One cis-regulatory element can regulate several genes, and conversely, one gene can have several cis-regulatory modules. Cis-regulatory modules are one of several types of functional regulatory elements. Regulatory elements are binding sites for transcription factors, which are involved in gene regulation. Cis-regulatory modules perform a large amount of developmental information processing. Cis-regulatory modules are non-random clusters at their specified target site that contain transcription factor binding sites. They are labeled as cis because they are typically located on the same DNA as the genes they control as opposed to trans
Trans-regulatory element
Trans-regulatory elements are genes which may modify the expression of distant genes. More specifically, trans-regulatory elements are DNA sequences that encode transcription factors....
, which refers to effects on genes not located on the same strand or farther away, such as transcription factors. The original definition presented cis-regulatory modules as enhancers of cis-acting DNA, which increased the rate of transcription from a linked promoter. However, this definition has changed to define cis-regulatory modules as a DNA sequence with transcription factor binding sites which are clustered into modular structures, including -but not limited to- locus control regions, promoters, enhancers, silencers, boundary control elements and other modulators. Cis-regulatory modules can be divided into classes. Enhancers regulate gene expression positively. Insulators work indirectly by interacting with other nearby cis-regulatory modules. Silencer
Silencer (DNA)
In genetics a silencer is a DNA sequence capable of binding transcription regulation factors termed repressors. Upon binding, RNA polymerase is prevented from initiating transcription thus decreasing or fully suppressing RNA synthesis....
s act by silencing genes. Cis-regulatory modules carry out their function by integrating the active transcription factors and the associated co-factors at a specific time and place in the cell, this information is read and an output is given.
Gene-regulation function of a
cis-regulatory module The design of cis-regulatory modules is such that transcription factorTranscription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s and epigenetic modification
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
s serve as inputs, and the output of the module is the command given to the transcription machinery, which in turn determines the rate of gene transcription or whether it is turned on or off. There are two types of transcription factor inputs: those that determine when the target gene is to be expressed and those that serve as functional drivers, which come into play only during specific situations during development. These inputs can come from different time points, can represent different signal ligands, or can come from different domains or lineages of cells. However, a lot still remains unknown. Additionally, the regulation of chromatin structure and nuclear organization also play a role in determining and controlling the function of cis-regulatory modules. Thus gene-regulation functions (GRF) provide a unique characteristic of a cis-regulatory module (CRM), relating the concentrations of transcription factors (input) to the promoter activities (output). The challenge is to predict GRFs. This challenge still remains unsolved. In general, gene-regulation functions do not use Boolean logic
Boolean logic
Boolean algebra is a logical calculus of truth values, developed by George Boole in the 1840s. It resembles the algebra of real numbers, but with the numeric operations of multiplication xy, addition x + y, and negation −x replaced by the respective logical operations of...
, although in some cases the approximation of the Boolean logic
Boolean logic
Boolean algebra is a logical calculus of truth values, developed by George Boole in the 1840s. It resembles the algebra of real numbers, but with the numeric operations of multiplication xy, addition x + y, and negation −x replaced by the respective logical operations of...
is still very useful.
The Boolean logic assumption
Within the assumption of the Boolean logic, four principles guiding the operation of these cis-regulatory modules are :1) The design of the cis-regulatory module determines the regulatory function.
2) In relation to development, these modules can generate both positive and negative outputs.
3) The output of each module is a product of the various operations performed on it. Common operations:
“OR” logic gate
Logic gate
A logic gate is an idealized or physical device implementing a Boolean function, that is, it performs a logical operation on one or more logic inputs and produces a single logic output. Depending on the context, the term may refer to an ideal logic gate, one that has for instance zero rise time and...
- This design indicates that in an output will be given when either input is given [3].
“AND” logic gate– In this design two different regulatory factors are necessary to make sure that a positive output results.
“Toggle Switches”- This design occurs when the signal ligand is absent while the transcription factor is present; this transcription factor ends up acting as a dominant repressor. However, once the signal ligand is present the transcription factor’s role as repressor is eliminated and transcription can occur.
Other Boolean logic
Boolean logic
Boolean algebra is a logical calculus of truth values, developed by George Boole in the 1840s. It resembles the algebra of real numbers, but with the numeric operations of multiplication xy, addition x + y, and negation −x replaced by the respective logical operations of...
operations can occur as well, such as sequence specific transcriptional repressors, which when they bind to the cis-regulatory module lead to an output of zero. Additionally, besides influence from the different logic operations, the output of a "cis"-regulatory module will also be influenced by prior events.
4) Cis-regulatory modules must interact with other regulatory elements. For the most part, even with the presence of functional overlap between cis-regulatory modules of a gene, the modules’ inputs and outputs tend to not be the same.
Identification and computational prediction of CRMs
Besides experimentally determining CRMs, there are various bioinformaticsBioinformatics
Bioinformatics is the application of computer science and information technology to the field of biology and medicine. Bioinformatics deals with algorithms, databases and information systems, web technologies, artificial intelligence and soft computing, information and computation theory, software...
algorithms for predicting them. Most algorithms try to search for significant combinations of transcription factor binding sites (DNA binding site
DNA binding site
DNA binding sites are a type of binding site found in DNA where other molecules may bind. DNA binding sites are distinct from other binding sites in that they are part of a DNA sequence and they are bound by DNA-binding proteins...
s) in promoter sequences of co-expressed genes. More advanced methods combine the search for significant motifs with correlation in gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
datasets between transcription factors and target genes.
Both methods have been implemented, for example, in the ModuleMaster.
Other programs created for the identification and prediction of "cis-regulatory modules include:
Stubb uses hidden Markov model
Markov model
In probability theory, a Markov model is a stochastic model that assumes the Markov property. Generally, this assumption enables reasoning and computation with the model that would otherwise be intractable.-Introduction:...
s to identify statistically significant clusters of transcription factor combinations. It also uses a second related genome to improve the prediction accuracy of the model.
Bayesian Network
Bayesian network
A Bayesian network, Bayes network, belief network or directed acyclic graphical model is a probabilistic graphical model that represents a set of random variables and their conditional dependencies via a directed acyclic graph . For example, a Bayesian network could represent the probabilistic...
s use an algorithm that combines site predictions and tissue-specific expression data for transcription factors and target genes of interest. This model also uses regression trees to depict the relationship between the identified cis-regulatory module and the possible binding set of transcription factors.
CRÈME examine clusters of target sites for transcription factors of interest. This program uses a database of confirmed transcription factor binding sites that were annotated across the human genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
. A search algorithm
Algorithm
In mathematics and computer science, an algorithm is an effective method expressed as a finite list of well-defined instructions for calculating a function. Algorithms are used for calculation, data processing, and automated reasoning...
is applied to the data set to identify possible combinations of transcription factors, which have binding sites that are close to the promoter of the gene set of interest. The possible cis-regulatory modules are then statistically analyzed and the significant combinations are graphically represented
Active cis-regulatory modules in a genomic sequence have been difficult to identify. Problems in identification arise because often scientists find themselves with a small set of known transcription factors, so it makes it harder to identify statistically significant clusters of transcription factor binding sites. Additionally, high costs limit the use of large whole genome tiling array
Tiling array
Tiling Arrays are a subtype of microarray chips. Like traditional microarrays, they function by hybridizing labeled DNA or RNA target molecules to probes fixed onto a solid surface. Tiling arrays differ from traditional microarrays in the nature of the probes...
s.
Classification of cis-regulatory modules
Cis-regulatory modules can be characterized by the information processing that they encode and the organization of their transcription factor binding sites. Additionally, cis-regulatory modules are also characterized by the way they affect the probability, proportion, and rate of transcription.Highly cooperative and coordinated cis-regulatory modules are classified as enhanceosome
Enhanceosome
The enhanceosome is a protein complex that binds to the "enhancer" region of a gene, found upstream or downstream, of the promoter, or within a gene. It accelerates the gene's transcription...
s. The architecture and the arrangement of the transcription factor binding sites are critical because disruption of the arrangement could cancel out the function.
Functional flexible cis-regulatory modules are called billboards. Their transcriptional output is the summation effect of the bound transcription factors.
Enhancers affect the probability of a gene being activated, but have little or no effect on rate.
Binary response model acts like an on/off switch for transcription. This model will increase or decrease the amount of cells that transcribe a gene, however it does not affect the rate of transcription.
Rheostatic response model describes cis-regulatory modules as regulators of the initiation rate of transcription of its associated gene.
Mode of action
Cis-regulatory modules can regulate their target genes over large distances, several models have been proposed to describe the way that these modules may communicate with their target gene promoter.DNA Scanning Model: In this model the transcription factor and cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
complex form at the cis-regulatory module and then continues to move along the DNA sequence until it finds the target gene promoter.
Looping Model: In this model the transcription factor binds to the cis-regulatory module, which then causes the looping of the DNA sequence and allows for the interaction with the target gene promoter.
Facilitated Tracking Model: This model combines parts of the two previous models. The transcription factor-cis-regulatory module complex causes the looping of the DNA sequence slowly towards the target promoter and forms a stable looped configuration.
Cis-regulatory module in gene regulatory network
The function of a gene regulatory networkGene regulatory network
A gene regulatory network or genetic regulatory network is a collection of DNA segments in a cell whichinteract with each other indirectly and with other substances in the cell, thereby governing the rates at which genes in the network are transcribed into mRNA.In general, each mRNA molecule goes...
depends on the architecture of the node
Node
In general, a node is a localised swelling or a point of intersection .Node may refer to:In mathematics:*Node , behaviour for an ordinary differential equation near a critical point...
s, whose function is dependent on the multiple cis-regulatory modules. The layout of cis-regulatory modules can provide enough information to generate spatial and temporal patterns of gene expression. During development each domain, where each domain represents a different spatial regions of the embryo, of gene expression will be under the control of different cis-regulatory module(s). The design of regulatory modules help in producing feedback
Feedback
Feedback describes the situation when output from an event or phenomenon in the past will influence an occurrence or occurrences of the same Feedback describes the situation when output from (or information about the result of) an event or phenomenon in the past will influence an occurrence or...
, feed forward, and cross-regulatory loops.
See also
- Regulation of gene expressionRegulation of gene expressionGene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
- Cis-regulatory elementCis-regulatory elementA cis-regulatory element or cis-element is a region of DNA or RNA that regulates the expression of genes located on that same molecule of DNA . This term is constructed from the Latin word cis, which means "on the same side as". These cis-regulatory elements are often binding sites for one or...
- Trans-regulatory elementTrans-regulatory elementTrans-regulatory elements are genes which may modify the expression of distant genes. More specifically, trans-regulatory elements are DNA sequences that encode transcription factors....
- Promoter
- EnhancerEnhancer (genetics)In genetics, an enhancer is a short region of DNA that can be bound with proteins to enhance transcription levels of genes in a gene cluster...
- OperonOperonIn genetics, an operon is a functioning unit of genomic DNA containing a cluster of genes under the control of a single regulatory signal or promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo trans-splicing to create...
- OperatorOperator (biology)In genetics, an operator is a segment of DNA to which a transcription factor protein binds. It is classically defined in the lac operon as a segment between the promoter and the genes of the operon. In the case of a repressor, the repressor protein physically obstructs the RNA polymerase from...