Conversion of a gene's sequence into a mature gene product or products
Gene expression
is the process by which information from a
gene
is used in the synthesis of a functional
gene product
that enables it to produce end products,
proteins
or
non-coding RNA
, and ultimately affect a
phenotype
. These products are often
proteins
, but in non-protein-coding genes such as
transfer RNA (tRNA)
and
small nuclear RNA (snRNA)
, the product is a functional
non-coding RNA
.
The process of gene expression is used by all known life?
eukaryotes
(including
multicellular organisms
),
prokaryotes
(
bacteria
and
archaea
), and utilized by
viruses
?to generate the
macromolecular
machinery for life.
In
genetics
, gene expression is the most fundamental level at which the
genotype
gives rise to the
phenotype
,
i.e.
observable trait. The genetic information stored in
DNA
represents the genotype, whereas the phenotype results from the "interpretation" of that information. Such phenotypes are often displayed by the synthesis of proteins that control the organism's structure and development, or that act as
enzymes
catalyzing specific metabolic pathways.
All steps in the gene expression process may be modulated (regulated), including the
transcription
,
RNA splicing
,
translation
, and
post-translational modification
of a protein.
Regulation of gene expression
gives control over the timing, location, and amount of a given gene product (protein or ncRNA) present in a cell and can have a profound effect on the cellular structure and function. Regulation of gene expression is the basis for
cellular differentiation
,
development
,
morphogenesis
and the versatility and
adaptability
of any
organism
. Gene regulation may therefore serve as a substrate for evolutionary change.
Mechanism
[
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]
Transcription
[
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]
The production of a RNA copy from a DNA strand is called
transcription
, and is performed by
RNA polymerases
, which add one
ribonucleotide
at a time to a growing RNA strand as per the
complementarity
law of the nucleotide bases. This RNA is
complementary
to the template 3′ → 5′ DNA strand,
[1]
with the exception that
thymines
(T) are replaced with
uracils
(U) in the RNA and possible errors.
In bacteria, transcription
is carried out by a single type of RNA polymerase, which needs to bind a DNA sequence called a
Pribnow box
with the help of the
sigma factor
protein (σ factor) to start transcription. In eukaryotes, transcription is performed in the nucleus by three types of RNA polymerases, each of which needs a special DNA sequence called the
promoter
and a set of DNA-binding proteins?
transcription factors
?to initiate the process (see regulation of transcription below).
RNA polymerase I
is responsible for transcription of ribosomal RNA (rRNA) genes.
RNA polymerase II
(Pol II) transcribes all protein-coding genes but also some non-coding RNAs (
e.g.
, snRNAs,
snoRNAs
or
long non-coding RNAs
).
RNA polymerase III
transcribes
5S rRNA
, transfer RNA (tRNA) genes, and some small non-coding RNAs (
e.g.
,
7SK
). Transcription ends when the polymerase encounters a sequence called the
terminator
.
mRNA processing
[
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]
While transcription of prokaryotic protein-coding genes creates
messenger RNA
(mRNA) that is ready for translation into protein, transcription of eukaryotic genes leaves a
primary transcript
of RNA (pre-RNA), which first has to undergo a series of modifications to become a mature RNA. Types and steps involved in the maturation processes vary between coding and non-coding preRNAs;
i.e.
even though preRNA molecules for both mRNA and
tRNA
undergo splicing, the steps and machinery involved are different.
[2]
The processing of non-coding RNA is described below (non-coding RNA maturation).
The processing of pre-mRNA include 5′
capping
, which is set of enzymatic reactions that add
7-methylguanosine
(m
7
G) to the 5′ end of pre-mRNA and thus protect the RNA from degradation by
exonucleases
. The m
7
G cap is then bound by
cap binding complex
heterodimer (CBC20/CBC80), which aids in mRNA export to cytoplasm and also protect the RNA from
decapping
.
Another modification is 3′
cleavage and polyadenylation
. They occur if polyadenylation signal sequence (5′- AAUAAA-3′) is present in pre-mRNA, which is usually between protein-coding sequence and terminator. The pre-mRNA is first cleaved and then a series of ~200 adenines (A) are added to form poly(A) tail, which protects the RNA from degradation. The poly(A) tail is bound by multiple
poly(A)-binding proteins (PABPs)
necessary for mRNA export and translation re-initiation. In the inverse process of deadenylation, poly(A) tails are shortened by the
CCR4-Not
3′-5′ exonuclease, which often leads to full transcript decay.
A very important modification of eukaryotic pre-mRNA is
RNA splicing
. The majority of eukaryotic pre-mRNAs consist of alternating segments called
exons
and
introns
. During the process of splicing, an RNA-protein catalytical complex known as
spliceosome
catalyzes two
transesterification
reactions, which remove an intron and release it in form of lariat structure, and then splice neighbouring exons together. In certain cases, some introns or exons can be either removed or retained in mature mRNA. This so-called
alternative splicing
creates series of different transcripts originating from a single gene. Because these transcripts can be potentially translated into different proteins, splicing extends the complexity of eukaryotic gene expression and the size of a species
proteome
.
Extensive RNA processing may be an
evolutionary advantage
made possible by the nucleus of eukaryotes. In prokaryotes, transcription and translation happen together, whilst in eukaryotes, the
nuclear membrane
separates the two processes, giving time for RNA processing to occur.
Non-coding RNA maturation
[
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]
In most organisms
non-coding genes (ncRNA)
are transcribed as precursors that undergo further processing. In the case of ribosomal RNAs (rRNA), they are often transcribed as a pre-rRNA that contains one or more rRNAs. The pre-rRNA is cleaved and modified (
2′-
O
-methylation
and
pseudouridine
formation) at specific sites by approximately 150 different small nucleolus-restricted RNA species, called snoRNAs. SnoRNAs associate with proteins, forming snoRNPs. While snoRNA part basepair with the target RNA and thus position the modification at a precise site, the protein part performs the catalytical reaction. In eukaryotes, in particular a snoRNP called RNase, MRP cleaves the 45S pre-rRNA into the
28S
,
5.8S
, and
18S rRNAs
. The rRNA and RNA processing factors form large aggregates called the
nucleolus
.
[3]
In the case of transfer RNA (tRNA), for example, the 5′ sequence is removed by
RNase P
,
[4]
whereas the 3′ end is removed by the
tRNase Z
enzyme
[5]
and the non-templated 3′ CCA tail is added by a
nucleotidyl transferase
.
[6]
In the case of
micro RNA (miRNA)
, miRNAs are first transcribed as primary transcripts or pri-miRNA with a cap and poly-A tail and processed to short, 70-nucleotide stem-loop structures known as pre-miRNA in the cell nucleus by the enzymes
Drosha
and
Pasha
. After being exported, it is then processed to mature miRNAs in the cytoplasm by interaction with the endonuclease
Dicer
, which also initiates the formation of the
RNA-induced silencing complex (RISC)
, composed of the
Argonaute
protein.
Even snRNAs and snoRNAs themselves undergo series of modification before they become part of functional RNP complex. This is done either in the nucleoplasm or in the specialized compartments called
Cajal bodies
. Their bases are methylated or pseudouridinilated by a group of
small Cajal body-specific RNAs (scaRNAs)
, which are structurally similar to snoRNAs.
RNA export
[
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]
In eukaryotes most mature RNA must be exported to the cytoplasm from the
nucleus
. While some RNAs function in the nucleus, many RNAs are transported through the
nuclear pores
and into the
cytosol
.
[7]
Export of RNAs requires association with specific proteins known as exportins. Specific exportin molecules are responsible for the export of a given RNA type. mRNA transport also requires the correct association with
Exon Junction Complex
(EJC), which ensures that correct processing of the mRNA is completed before export. In some cases RNAs are additionally transported to a specific part of the cytoplasm, such as a
synapse
; they are then towed by
motor proteins
that bind through linker proteins to specific sequences (called "zipcodes") on the RNA.
[8]
Translation
[
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]
For some non-coding RNA, the mature RNA is the final gene product.
[9]
In the case of messenger RNA (mRNA) the RNA is an information carrier coding for the synthesis of one or more proteins. mRNA carrying a single protein sequence (common in eukaryotes) is
monocistronic
whilst mRNA carrying multiple protein sequences (common in prokaryotes) is known as
polycistronic
.
Every mRNA consists of three parts: a 5′ untranslated region (5′UTR), a protein-coding region or
open reading frame
(ORF), and a 3′ untranslated region (3′UTR). The coding region carries information for protein synthesis encoded by the
genetic code
to form triplets. Each triplet of nucleotides of the
coding region
is called a
codon
and corresponds to a binding site complementary to an anticodon triplet in transfer RNA. Transfer RNAs with the same anticodon sequence always carry an identical type of
amino acid
. Amino acids are then chained together by the
ribosome
according to the order of triplets in the coding region. The ribosome helps transfer RNA to bind to messenger RNA and takes the amino acid from each transfer RNA and makes a structure-less protein out of it.
[10]
[11]
Each mRNA molecule is translated into many protein molecules, on average ~2800 in mammals.
[12]
[13]
In prokaryotes translation generally occurs at the point of transcription (co-transcriptionally), often using a messenger RNA that is still in the process of being created. In eukaryotes translation can occur in a variety of regions of the cell depending on where the protein being written is supposed to be. Major locations are the
cytoplasm
for soluble cytoplasmic proteins and the membrane of the
endoplasmic reticulum
for proteins that are for export from the cell or insertion into a cell
membrane
. Proteins that are supposed to be produced at the endoplasmic reticulum are recognised part-way through the translation process. This is governed by the
signal recognition particle
?a protein that binds to the ribosome and directs it to the endoplasmic reticulum when it finds a
signal peptide
on the growing (nascent) amino acid chain.
[14]
Folding
[
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]
Each
protein
exists as an unfolded
polypeptide
or random coil when translated from a sequence of
mRNA
into a linear chain of
amino acids
. This polypeptide lacks any developed three-dimensional structure (the left hand side of the neighboring figure). The polypeptide then folds into its characteristic and functional
three-dimensional structure
from a
random coil
.
[15]
Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein (the right hand side of the figure) known as the
native state
. The resulting three-dimensional structure is determined by the amino acid sequence (
Anfinsen's dogma
).
[16]
The correct three-dimensional structure is essential to function, although some parts of functional proteins
may remain unfolded
.
[17]
Failure to fold into the intended shape usually produces inactive proteins with different properties including toxic
prions
. Several
neurodegenerative
and other
diseases
are believed to result from the accumulation of
misfolded
proteins.
[18]
Many
allergies
are caused by the folding of the proteins, for the immune system does not produce antibodies for certain protein structures.
[19]
Enzymes called
chaperones
assist the newly formed protein to attain (
fold
into) the 3-dimensional structure it needs to function.
[20]
Similarly, RNA chaperones help RNAs attain their functional shapes.
[21]
Assisting protein folding is one of the main roles of the endoplasmic reticulum in eukaryotes.
Translocation
[
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]
Secretory proteins of eukaryotes or prokaryotes must be translocated to enter the secretory pathway. Newly synthesized proteins are directed to the eukaryotic Sec61 or prokaryotic SecYEG translocation channel by
signal peptides
. The efficiency of protein secretion in eukaryotes is very dependent on the
signal peptide
which has been used.
[22]
Protein transport
[
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]
Many proteins are destined for other parts of the cell than the cytosol and a wide range of signalling sequences or
(signal peptides)
are used to direct proteins to where they are supposed to be. In prokaryotes this is normally a simple process due to limited compartmentalisation of the cell. However, in eukaryotes there is a great variety of different targeting processes to ensure the protein arrives at the correct organelle.
Not all proteins remain within the cell and many are exported, for example,
digestive enzymes
,
hormones
and
extracellular matrix
proteins. In eukaryotes the export pathway is well developed and the main mechanism for the export of these proteins is translocation to the endoplasmic reticulum, followed by transport via the
Golgi apparatus
.
[23]
[24]
Regulation of gene expression
[
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]
Regulation of gene expression is the control of the amount and timing of appearance of the functional product of a gene. Control of expression is vital to allow a cell to produce the gene products it needs when it needs them; in turn, this gives cells the flexibility to adapt to a variable environment, external signals, damage to the cell, and other stimuli. More generally, gene regulation gives the cell control over all structure and function, and is the basis for
cellular differentiation
,
morphogenesis
and the versatility and adaptability of any organism.
Numerous terms are used to describe types of genes depending on how they are regulated; these include:
- A
constitutive gene
is a gene that is transcribed continually as opposed to a facultative gene, which is only transcribed when needed.
- A
housekeeping gene
is a gene that is required to maintain basic cellular function and so is typically expressed in all cell types of an organism. Examples include
actin
,
GAPDH
and
ubiquitin
. Some housekeeping genes are transcribed at a relatively constant rate and these genes can be used as a reference point in experiments to measure the expression rates of other genes.
- A
facultative gene
is a gene only transcribed when needed as opposed to a constitutive gene.
- An
inducible gene
is a gene whose expression is either responsive to environmental change or dependent on the position in the cell cycle.
Any step of gene expression may be modulated, from the DNA-RNA transcription step to
post-translational modification
of a protein. The stability of the final gene product, whether it is RNA or protein, also contributes to the expression level of the gene?an unstable product results in a low expression level. In general gene expression is regulated through changes
[25]
in the number and type of interactions between molecules
[26]
that collectively influence transcription of DNA
[27]
and translation of RNA.
[28]
Some simple examples of where gene expression is important are:
Transcriptional regulation
[
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]
Regulation of transcription
can be broken down into three main routes of influence; genetic (direct interaction of a control factor with the gene), modulation interaction of a control factor with the transcription machinery and epigenetic (non-sequence changes in DNA structure that influence transcription).
Direct interaction with DNA is the simplest and the most direct method by which a protein changes transcription levels. Genes often have several protein binding sites around the coding region with the specific function of regulating transcription. There are many classes of regulatory DNA binding sites known as
enhancers
,
insulators
and
silencers
. The mechanisms for regulating transcription are varied, from blocking key binding sites on the DNA for
RNA polymerase
to acting as an
activator
and promoting transcription by assisting RNA polymerase binding.
The activity of transcription factors is further modulated by intracellular signals causing protein post-translational modification including
phosphorylation
,
acetylation
, or
glycosylation
. These changes influence a transcription factor's ability to bind, directly or indirectly, to promoter DNA, to recruit RNA polymerase, or to favor elongation of a newly synthesized RNA molecule.
The nuclear membrane in eukaryotes allows further regulation of transcription factors by the duration of their presence in the nucleus, which is regulated by reversible changes in their structure and by binding of other proteins.
[29]
Environmental stimuli or endocrine signals
[30]
may cause modification of regulatory proteins
[31]
eliciting cascades of intracellular signals,
[32]
which result in regulation of gene expression.
It has become apparent that there is a significant influence of non-DNA-sequence specific effects on transcription. These effects are referred to as
epigenetic
and involve the higher order structure of DNA, non-sequence specific DNA binding proteins and chemical modification of DNA. In general epigenetic effects alter the accessibility of DNA to proteins and so modulate transcription.
In eukaryotes the structure of
chromatin
, controlled by the
histone code
, regulates access to DNA with significant impacts on the expression of genes in
euchromatin
and
heterochromatin
areas.
Enhancers, transcription factors, mediator complex and DNA loops in mammalian transcription
[
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]
Gene expression in mammals is regulated by many
cis-regulatory elements
, including
core promoters and promoter-proximal elements
that are located near the
transcription start sites
of genes,
upstream
on the DNA (towards the 5' region of the
sense strand
). Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include
enhancers
,
silencers
,
insulators
and tethering elements.
[33]
Enhancers and their associated
transcription factors
have a leading role in the regulation of gene expression.
[34]
Enhancers
are genome regions that regulate genes. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes.
[35]
Multiple enhancers, each often tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control gene expression.
[35]
The illustration shows an enhancer looping around to come into proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of
CTCF
or
YY1
). One member of the dimer is anchored to its binding motif on the enhancer and the other member is anchored to its binding motif on the promoter (represented by the red zigzags in the illustration).
[36]
Several cell function-specific transcription factors (among the about 1,600 transcription factors in a human cell)
[37]
generally bind to specific motifs on an enhancer.
[38]
A small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern transcription level of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter.
[39]
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in the figure.
[40]
An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration).
[41]
An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene.
[42]
DNA methylation and demethylation in transcriptional regulation
[
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]
DNA methylation
is a widespread mechanism for epigenetic influence on gene expression and is seen in
bacteria
and
eukaryotes
and has roles in heritable transcription silencing and transcription regulation. Methylation most often occurs on a cytosine (see Figure). Methylation of cytosine primarily occurs in dinucleotide sequences where a cytosine is followed by a guanine, a
CpG site
. The number of
CpG sites
in the human genome is about 28 million.
[43]
Depending on the type of cell, about 70% of the CpG sites have a methylated cytosine.
[44]
Methylation of cytosine in DNA has a major role in regulating gene expression. Methylation of CpGs in a promoter region of a gene usually represses gene transcription
[45]
while methylation of CpGs in the body of a gene increases expression.
[46]
TET enzymes
play a central role in demethylation of methylated cytosines. Demethylation of CpGs in a gene promoter by
TET enzyme
activity increases transcription of the gene.
[47]
Transcriptional regulation in learning and memory
[
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]
In a rat, contextual
fear conditioning
(CFC) is a painful learning experience. Just one episode of CFC can result in a life-long fearful memory.
[48]
After an episode of CFC, cytosine methylation is altered in the promoter regions of about 9.17% of all genes in the
hippocampus
neuron DNA of a rat.
[49]
The
hippocampus
is where new memories are initially stored. After CFC about 500 genes have increased transcription (often due to demethylation of CpG sites in a promoter region) and about 1,000 genes have decreased transcription (often due to newly formed 5-methylcytosine at CpG sites in a promoter region). The pattern of induced and repressed genes within neurons appears to provide a molecular basis for forming the first transient memory of this training event in the hippocampus of the rat brain.
[49]
Some specific mechanisms guiding new DNA methylations and new
DNA demethylations
in the
hippocampus
during memory establishment have been established (see
[50]
for summary). One mechanism includes guiding the short isoform of the
TET1
DNA demethylation
enzyme, TET1s, to about 600 locations on the genome. The guidance is performed by association of TET1s with
EGR1
protein, a transcription factor important in memory formation. Bringing TET1s to these locations initiates DNA demethylation at those sites, up-regulating associated genes. A second mechanism involves DNMT3A2, a splice-isoform of
DNA methyltransferase
DNMT3A, which adds methyl groups to cytosines in DNA. This isoform is induced by synaptic activity, and its location of action appears to be determined by
histone
post-translational modifications (a
histone code
). The resulting new
messenger RNAs
are then transported by
messenger RNP
particles (neuronal granules) to synapses of the neurons, where they can be translated into proteins affecting the activities of synapses.
[50]
In particular, the
brain-derived neurotrophic factor
gene (
BDNF
) is known as a "learning gene".
[51]
After CFC there was upregulation of
BDNF
gene expression, related to decreased CpG methylation of certain internal promoters of the gene, and this was correlated with learning.
[51]
Transcriptional regulation in cancer
[
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]
The majority of gene
promoters
contain a
CpG island
with numerous
CpG sites
.
[52]
When many of a gene's promoter CpG sites are
methylated
the gene becomes silenced.
[53]
Colorectal cancers typically have 3 to 6
driver
mutations and 33 to 66
hitchhiker
or passenger mutations.
[54]
However, transcriptional silencing may be of more importance than mutation in causing progression to cancer. For example, in colorectal cancers about 600 to 800 genes are transcriptionally silenced by CpG island methylation (see
regulation of transcription in cancer
). Transcriptional repression in cancer can also occur by other
epigenetic
mechanisms, such as altered expression of
microRNAs
.
[55]
In breast cancer, transcriptional repression of
BRCA1
may occur more frequently by over-transcribed microRNA-182 than by hypermethylation of the BRCA1 promoter (see
Low expression of BRCA1 in breast and ovarian cancers
).
Post-transcriptional regulation
[
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]
In eukaryotes, where export of RNA is required before translation is possible, nuclear export is thought to provide additional control over gene expression. All transport in and out of the nucleus is via the
nuclear pore
and transport is controlled by a wide range of
importin
and
exportin
proteins.
Expression of a gene coding for a protein is only possible if the messenger RNA carrying the code survives long enough to be translated. In a typical cell, an RNA molecule is only stable if specifically protected from degradation. RNA degradation has particular importance in regulation of expression in eukaryotic cells where mRNA has to travel significant distances before being translated. In eukaryotes, RNA is stabilised by certain post-transcriptional modifications, particularly the
5′ cap
and
poly-adenylated tail
.
Intentional degradation of mRNA is used not just as a defence mechanism from foreign RNA (normally from viruses) but also as a route of mRNA
destabilisation
. If an mRNA molecule has a complementary sequence to a
small interfering RNA
then it is targeted for destruction via the
RNA interference
pathway.
Three prime untranslated regions and microRNAs
[
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]
Three prime untranslated regions
(3′UTRs) of
messenger RNAs
(mRNAs) often contain regulatory sequences that post-transcriptionally influence gene expression. Such 3′-UTRs often contain both binding sites for
microRNAs
(miRNAs) as well as for regulatory proteins. By binding to specific sites within the 3′-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript. The 3′-UTR also may have silencer regions that bind repressor proteins that inhibit the expression of a mRNA.
The 3′-UTR often contains
microRNA response elements (MREs)
. MREs are sequences to which miRNAs bind. These are prevalent motifs within 3′-UTRs. Among all regulatory motifs within the 3′-UTRs (e.g. including silencer regions), MREs make up about half of the motifs.
As of 2014, the
miRBase
web site,
[56]
an archive of
miRNA
sequences
and annotations, listed 28,645 entries in 233 biologic species. Of these, 1,881 miRNAs were in annotated human miRNA loci. miRNAs were predicted to have an average of about four hundred target
mRNAs
(affecting expression of several hundred genes).
[57]
Friedman et al.
[57]
estimate that >45,000 miRNA target sites within human mRNA 3′UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs.
Direct experiments show that a single miRNA can reduce the stability of hundreds of unique mRNAs.
[58]
Other experiments show that a single miRNA may repress the production of hundreds of proteins, but that this repression often is relatively mild (less than 2-fold).
[59]
[60]
The effects of miRNA dysregulation of gene expression seem to be important in cancer.
[61]
For instance, in gastrointestinal cancers, nine miRNAs have been identified as
epigenetically
altered and effective in down regulating DNA repair enzymes.
[62]
The effects of miRNA dysregulation of gene expression also seem to be important in neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depression, Parkinson's disease, Alzheimer's disease and autism spectrum disorders.
[63]
[64]
Translational regulation
[
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]
Direct regulation of translation is less prevalent than control of transcription or mRNA stability but is occasionally used. Inhibition of protein translation is a major target for
toxins
and
antibiotics
, so they can kill a cell by overriding its normal gene expression control.
Protein synthesis inhibitors
include the antibiotic
neomycin
and the toxin
ricin
.
Post-translational modifications
[
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]
Post-translational modifications (PTMs) are
covalent
modifications to proteins. Like RNA splicing, they help to significantly diversify the proteome. These modifications are usually catalyzed by enzymes. Additionally, processes like covalent additions to amino acid side chain residues can often be reversed by other enzymes. However, some, like the
proteolytic cleavage
of the protein backbone, are irreversible.
[65]
PTMs play many important roles in the cell.
[66]
For example, phosphorylation is primarily involved in activating and deactivating proteins and in signaling pathways.
[67]
PTMs are involved in transcriptional regulation: an important function of acetylation and methylation is histone tail modification, which alters how accessible DNA is for transcription.
[65]
They can also be seen in the immune system, where glycosylation plays a key role.
[68]
One type of PTM can initiate another type of PTM, as can be seen in how
ubiquitination
tags proteins for degradation through proteolysis.
[65]
Proteolysis, other than being involved in breaking down proteins, is also important in activating and deactivating them, and in regulating biological processes such as DNA transcription and cell death.
[69]
Measurement
[
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]
Measuring gene expression is an important part of many
life sciences
, as the ability to quantify the level at which a particular gene is expressed within a cell, tissue or organism can provide a lot of valuable information. For example, measuring gene expression can:
Similarly, the analysis of the location of protein expression is a powerful tool, and this can be done on an organismal or cellular scale. Investigation of localization is particularly important for the study of
development
in multicellular organisms and as an indicator of protein function in single cells. Ideally, measurement of expression is done by detecting the final gene product (for many genes, this is the protein); however, it is often easier to detect one of the precursors, typically
mRNA
and to infer gene-expression levels from these measurements.
mRNA quantification
[
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]
Levels of mRNA can be quantitatively measured by
northern blotting
, which provides size and sequence information about the mRNA molecules. A sample of RNA is separated on an
agarose gel
and hybridized to a radioactively labeled RNA probe that is complementary to the target sequence. The radiolabeled RNA is then detected by an
autoradiograph
. Because the use of radioactive reagents makes the procedure time-consuming and potentially dangerous, alternative labeling and detection methods, such as digoxigenin and biotin chemistries, have been developed. Perceived disadvantages of Northern blotting are that large quantities of RNA are required and that quantification may not be completely accurate, as it involves measuring band strength in an image of a gel. On the other hand, the additional mRNA size information from the Northern blot allows the discrimination of alternately spliced transcripts.
Another approach for measuring mRNA abundance is RT-qPCR. In this technique,
reverse transcription
is followed by
quantitative PCR
. Reverse transcription first generates a DNA template from the mRNA; this single-stranded template is called
cDNA
. The cDNA template is then amplified in the quantitative step, during which the
fluorescence
emitted by labeled
hybridization probes
or
intercalating dyes
changes as the
DNA amplification
process progresses. With a carefully constructed standard curve, qPCR can produce an absolute measurement of the number of copies of original mRNA, typically in units of copies per nanolitre of homogenized tissue or copies per cell. qPCR is very sensitive (detection of a single mRNA molecule is theoretically possible), but can be expensive depending on the type of reporter used; fluorescently labeled oligonucleotide probes are more expensive than non-specific intercalating fluorescent dyes.
For
expression profiling
, or high-throughput analysis of many genes within a sample,
quantitative PCR
may be performed for hundreds of genes simultaneously in the case of low-density arrays. A second approach is the
hybridization microarray
. A single array or "chip" may contain probes to determine transcript levels for every known gene in the genome of one or more organisms. Alternatively, "tag based" technologies like
Serial analysis of gene expression
(SAGE) and
RNA-Seq
, which can provide a relative measure of the cellular
concentration
of different mRNAs, can be used. An advantage of tag-based methods is the "open architecture", allowing for the exact measurement of any transcript, with a known or unknown sequence. Next-generation sequencing (NGS) such as
RNA-Seq
is another approach, producing vast quantities of sequence data that can be matched to a reference genome. Although NGS is comparatively time-consuming, expensive, and resource-intensive, it can identify
single-nucleotide polymorphisms
, splice-variants, and novel genes, and can also be used to profile expression in organisms for which little or no sequence information is available.
RNA profiles in Wikipedia
[
edit
]
Profiles like these are found for almost all proteins listed in Wikipedia. They are generated by organizations such as the
Genomics Institute of the Novartis Research Foundation
and the
European Bioinformatics Institute
. Additional information can be found by searching their databases (for an example of the GLUT4 transporter pictured here, see citation).
[70]
These profiles indicate the level of DNA expression (and hence RNA produced) of a certain protein in a certain tissue, and are color-coded accordingly in the images located in the Protein Box on the right side of each Wikipedia page.
Protein quantification
[
edit
]
For genes encoding proteins, the expression level can be directly assessed by a number of methods with some clear analogies to the techniques for mRNA quantification.
One of the most commonly used methods is to perform a
Western blot
against the protein of interest.
[71]
This gives information on the size of the protein in addition to its identity. A sample (often cellular
lysate
) is separated on a
polyacrylamide gel
, transferred to a membrane and then probed with an
antibody
to the protein of interest. The antibody can either be conjugated to a
fluorophore
or to
horseradish peroxidase
for imaging and/or quantification. The gel-based nature of this assay makes quantification less accurate, but it has the advantage of being able to identify later modifications to the protein, for example proteolysis or ubiquitination, from changes in size.
mRNA-protein correlation
[
edit
]
While transcription directly reflects gene expression, the copy number of mRNA molecules does not directly correlate with the number of protein molecules translated from mRNA. Quantification of both protein and mRNA permits a correlation of the two levels. Regulation on each step of gene expression can impact the correlation, as shown for regulation of translation
[13]
or protein stability.
[72]
Post-translational factors, such as protein transport in highly polar cells,
[73]
can influence the measured mRNA-protein correlation as well.
Localization
[
edit
]
Analysis of expression is not limited to quantification; localization can also be determined. mRNA can be detected with a suitably labelled complementary mRNA strand and protein can be detected via labelled antibodies. The probed sample is then observed by microscopy to identify where the mRNA or protein is.
By replacing the gene with a new version fused to a
green fluorescent protein
marker or similar, expression may be directly quantified in live cells. This is done by imaging using a
fluorescence microscope
. It is very difficult to clone a GFP-fused protein into its native location in the genome without affecting expression levels, so this method often cannot be used to measure endogenous gene expression. It is, however, widely used to measure the expression of a gene artificially introduced into the cell, for example via an
expression vector
. By fusing a target protein to a fluorescent reporter, the protein's behavior, including its cellular localization and expression level, can be significantly changed.
The
enzyme-linked immunosorbent assay
works by using antibodies immobilised on a
microtiter plate
to capture proteins of interest from samples added to the well. Using a detection antibody conjugated to an enzyme or fluorophore the quantity of bound protein can be accurately measured by
fluorometric
or
colourimetric
detection. The detection process is very similar to that of a Western blot, but by avoiding the gel steps more accurate quantification can be achieved.
Expression system
[
edit
]
An expression system is a system specifically designed for the production of a gene product of choice. This is normally a protein although may also be RNA, such as
tRNA
or a
ribozyme
. An expression system consists of a gene, normally encoded by
DNA
, and the
molecular machinery
required to
transcribe
the DNA into
mRNA
and
translate
the mRNA into
protein
using the reagents provided. In the broadest sense this includes every living cell but the term is more normally used to refer to expression as a laboratory tool. An expression system is therefore often artificial in some manner. Expression systems are, however, a fundamentally natural process. Viruses are an excellent example where they replicate by using the host cell as an expression system for the viral proteins and genome.
Inducible expression
[
edit
]
Doxycycline
is also used in "Tet-on" and "Tet-off"
tetracycline controlled transcriptional activation
to regulate
transgene
expression in organisms and
cell cultures
.
In nature
[
edit
]
In addition to these biological tools, certain naturally observed configurations of DNA (genes, promoters, enhancers, repressors) and the associated machinery itself are referred to as an expression system. This term is normally used in the case where a gene or set of genes is switched on under well defined conditions, for example, the simple repressor switch expression system in
Lambda phage
and the
lac operator
system in bacteria. Several natural expression systems are directly used or modified and used for artificial expression systems such as the
Tet-on and Tet-off
expression system.
Gene networks
[
edit
]
Genes have sometimes been regarded as nodes in a network, with inputs being proteins such as
transcription factors
, and outputs being the level of gene expression. The node itself performs a function, and the operation of these functions have been interpreted as performing a kind of information processing within cells and determines cellular behavior.
Gene networks can also be constructed without formulating an explicit causal model. This is often the case when assembling networks from large expression data sets.
[74]
Covariation and correlation of expression is computed across a large sample of cases and measurements (often
transcriptome
or
proteome
data). The source of variation can be either experimental or natural (observational). There are several ways to construct gene expression networks, but one common approach is to compute a matrix of all pair-wise correlations of expression across conditions, time points, or individuals and convert the matrix (after thresholding at some cut-off value) into a graphical representation in which nodes represent genes, transcripts, or proteins and edges connecting these nodes represent the strength of association (see
GeneNetwork GeneNetwork 2
).
[75]
Techniques and tools
[
edit
]
The following experimental techniques are used to measure gene expression and are listed in roughly chronological order, starting with the older, more established technologies. They are divided into two groups based on their degree of
multiplexity
.
- Low-to-mid-plex techniques:
- Higher-plex techniques:
Gene expression databases
[
edit
]
See also
[
edit
]
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