Gene silencing
Gene silencing is the regulation of gene expression in a cell to prevent the expression of a
[1][2]
[2] Gene silencing can occur during either transcription or translation and is often
certain gene
gene..[1]
used in research.[1][2] In particular, methods used to silence genes are being increasingly used to
produce therapeutics to combat cancer and other diseases, such as infectious diseases and
neurodegenerative disorders.
Gene silencing is often considered the same as gene knockdown.[3][4] When genes are silenced,
their expression is reduced.[3][4] In contrast, when genes are knocked out, they are completely
erased from the organism's genome and, thus, have no expression.[3][4] Gene silencing is
considered a gene knockdown mechanism since the methods used to silence genes, such as
RNAi, CRISPR, or siRNA, generally reduce the expression of a gene by at least 70% but do not
eliminate it. Methods using gene silencing are often considered better than gene knockouts
since they allow researchers to study essential genes that are required for the animal models to
survive and cannot be removed. In addition, they provide a more complete view on the
development of diseases since diseases are generally associated with genes that have a
reduced expression.[3]
Types
Transcriptional
Genomic Imprinting
Paramutation
Transposon silencing (or Histone Modifications)
Transgene silencing
Position effect
RNA-directed DNA methylation
Post-transcriptional
RNA interference
RNA silencing
Nonsense mediated decay
Meiotic
Transvection
Meiotic silencing of unpaired DNA
Research methods
Antisense oligonucleotides
Antisense oligonucleotides were discovered in 1978 by Paul Zamecnik and Mary Stephenson.[5]
Oligonucleotides, which are short nucleic acid fragments, bind to complementary target mRNA
molecules when added to the cell.[5][6] These molecules can be composed of single-stranded
DNA or RNA and are generally 13–25 nucleotides long.[6][7] The antisense oligonucleotides can
affect gene expression in two ways: by using an RNase H-dependent mechanism or by using a
steric blocking mechanism.[6][7] RNase H-dependent oligonucleotides cause the target mRNA
molecules to be degraded, while steric-blocker oligonucleotides prevent translation of the mRNA
molecule.[6][7] The majority of antisense drugs function through the RNase H-dependent
mechanism, in which RNase H hydrolyzes the RNA strand of the DNA/RNA heteroduplex.[6][7]
expression.[6]
Ribozymes
General mechanism utilized by ribozymes to cleave RNA molecules
Ribozymes are catalytic RNA molecules used to inhibit gene expression. These molecules work
by cleaving mRNA molecules, essentially silencing the genes that produced them. Sidney Altman
and Thomas Cech first discovered catalytic RNA molecules, RNase P and group II intron
ribozymes, in 1989 and won the Nobel Prize for their discovery.[8][9] Several types of ribozyme
motifs exist, including hammerhead, hairpin, hepatitis delta virus, group I, group II, and RNase P
ribozymes. Hammerhead, hairpin, and hepatitis delta virus (HDV) ribozyme motifs are generally
found in viruses or viroid RNAs.[8] These motifs are able to self-cleave a specific phosphodiester
bond on an mRNA molecule.[8] Lower eukaryotes and a few bacteria contain group I and group II
ribozymes.[8] These motifs can self-splice by cleaving and joining phosphodiester bonds.[8] The
last ribozyme motif, the RNase P ribozyme, is found in Escherichia coli and is known for its ability
to cleave the phosphodiester bonds of several tRNA precursors when joined to a protein
cofactor.[8]
The general catalytic mechanism used by ribozymes is similar to the mechanism used by
protein ribonucleases.[10] These catalytic RNA molecules bind to a specific site and attack the
neighboring phosphate in the RNA backbone with their 2' oxygen, which acts as a nucleophile,
resulting in the formation of cleaved products with a 2'3'-cyclic phosphate and a 5' hydroxyl
terminal end.[10] This catalytic mechanism has been increasingly used by scientists to perform
sequence-specific cleavage of target mRNA molecules. In addition, attempts are being made to
use ribozymes to produce gene silencing therapeutics, which would silence genes that are
responsible for causing diseases.[11]
RNA interference
Left:Overview of RNA interference.
RNA interference (RNAi) is a natural process used by cells to regulate gene expression. It was
discovered in 1998 by Andrew Fire and Craig Mello, who won the Nobel Prize for their discovery
in 2006.[12] The process to silence genes first begins with the entrance of a double-stranded RNA
(dsRNA) molecule into the cell, which triggers the RNAi pathway.[12] The double-stranded
molecule is then cut into small double-stranded fragments by an enzyme called Dicer.[12] These
small fragments, which include small interfering RNAs (siRNA) and microRNA (miRNA), are
approximately 21–23 nucleotides in length.[12][13] The fragments integrate into a multi-subunit
protein called the RNA-induced silencing complex, which contains Argonaute proteins that are
essential components of the RNAi pathway.[12][13] One strand of the molecule, called the "guide"
strand, binds to RISC, while the other strand, known as the "passenger" strand is degraded.[12][13]
The guide or antisense strand of the fragment that remains bound to RISC directs the sequencespecific silencing of the target mRNA molecule.[13] The genes can be silenced by siRNA
molecules that cause the endonucleatic cleavage of the target mRNA molecules or by miRNA
molecules that suppress translation of the mRNA molecule.[13] With the cleavage or translational
repression of the mRNA molecules, the genes that form them are rendered essentially
inactive.[12] RNAi is thought to have evolved as a cellular defense mechanism against invaders,
such as RNA viruses, or to combat the proliferation of transposons within a cell's DNA.[12] Both
RNA viruses and transposons can exist as double-stranded RNA and lead to the activation of
RNAi.[12] Currently, siRNAs are being widely used to suppress specific gene expression and to
assess the function of genes. Companies utilizing this approach include Alnylam, Sanofi,[14]
Arrowhead, Discerna,[15] and Persomics,[16] among others.
Three prime untranslated regions and microRNAs
The three prime untranslated regions (3'UTRs) of messenger RNAs (mRNAs) often contain
regulatory sequences that post-transcriptionally cause gene silencing. 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, a large number of specific miRNAs decrease gene expression
of their particular target mRNAs by either inhibiting translation or directly causing degradation of
the transcript, using a mechanism similar to RNA interference (see MicroRNA). The 3'-UTR also
may have silencer regions that bind repressor proteins that inhibit the expression of an mRNA.
The 3'-UTR often contains microRNA response elements (MREs). MREs are sequences to which
miRNAs bind and cause gene silencing. 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,[17] 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 each have an average of about four hundred target mRNAs
(causing gene silencing of several hundred genes).[18] Freidman et al.[18] 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.[19] 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).[20][21]
The effects of miRNA dysregulation of gene expression seem to be important in cancer.[22] For
instance, in gastrointestinal cancers, nine miRNAs have been identified as epigenetically altered
and effective in down regulating DNA repair enzymes.[23]
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.[24][25][26]
Applications
Medical research
Gene silencing techniques have been widely used by researchers to study genes associated with
disorders. These disorders include cancer, infectious diseases, respiratory diseases, and
neurodegenerative disorders. Gene silencing is also currently being used in drug discovery
efforts, such as synthetic lethality, high-throughput screening, and miniaturized RNAi screens.
Cancer
RNA interference has been used to silence genes associated with several cancers. In in vitro
studies of chronic myelogenous leukemia (CML), siRNA was used to cleave the fusion protein,
BCR-ABL, which prevents the drug Gleevec (imatinib) from binding to the cancer cells.[27]
Cleaving the fusion protein reduced the amount of transformed hematopoietic cells that spread
throughout the body by increasing the sensitivity of the cells to the drug.[27] RNA interference
can also be used to target specific mutants. For instance, siRNAs were able to bind specifically
to tumor suppressor p53 molecules containing a single point mutation and destroy it, while
leaving the wild-type suppressor intact.[28]
Receptors involved in mitogenic pathways that lead to the increased production of cancer cells
there have also been targeted by siRNA molecules. The chemokine receptor chemokine receptor
4 (CXCR4), associated with the proliferation of breast cancer, was cleaved by siRNA molecules
that reduced the number of divisions commonly observed by the cancer cells.[29] Researchers
have also used siRNAs to selectively regulate the expression of cancer-related genes.
Antiapoptotic proteins, such as clusterin and survivin, are often expressed in cancer cells.[30][31]
Clusterin and survivin-targeting siRNAs were used to reduce the number of antiapoptotic
proteins and, thus, increase the sensitivity of the cancer cells to chemotherapy treatments.[30][31]
In vivo studies are also being increasingly utilized to study the potential use of siRNA molecules
in cancer therapeutics. For instance, mice implanted with colon adenocarcinoma cells were
found to survive longer when the cells were pretreated with siRNAs that targeted B-catenin in the
cancer cells.[32]
Infectious disease
Viruses
Viral genes and host genes that are required for viruses to replicate or enter the cell, or that play
an important role in the life cycle of the virus are often targeted by antiviral therapies. RNAi has
been used to target genes in several viral diseases, such as the human immunodeficiency virus
(HIV) and hepatitis.[33][34] In particular, siRNA was used to silence the primary HIV receptor
chemokine receptor 5 (CCR5).[35] This prevented the virus from entering the human peripheral
blood lymphocytes and the primary hematopoietic stem cells.[35][36] A similar technique was
used to decrease the amount of the detectable virus in hepatitis B and C infected cells. In
hepatitis B, siRNA silencing was used to target the surface antigen on the hepatitis B virus and
led to a decrease in the number of viral components.[37] In addition, siRNA techniques used in
hepatitis C were able to lower the amount of the virus in the cell by 98%.[38][39]
RNA interference has been in commercial use to control virus diseases of plants for over 20
years (see Plant disease resistance). In 1986–1990, multiple examples of "coat proteinmediated resistance" against plant viruses were published, before RNAi had been discovered.[40]
In 1993, work with tobacco etch virus first demonstrated that host organisms can target specific
virus or mRNA sequences for degradation, and that this activity is the mechanism behind some
examples of virus resistance in transgenic plants.[41][42] The discovery of small interfering RNAs
(the specificity determinant in RNA-mediated gene silencing) also utilized virus-induced posttranscriptional gene silencing in plants.[43] By 1994, transgenic squash varieties had been
generated expressing coat protein genes from three different viruses, providing squash hybrids
with field-validated multiviral resistance that remain in commercial use at present. Potato lines
expressing viral replicase sequences that confer resistance to potato leafroll virus were sold
under the trade names NewLeaf Y and NewLeaf Plus, and were widely accepted in commercial
production in 1999–2001, until McDonald's Corp. decided not to purchase GM potatoes and
Monsanto decided to close their NatureMark potato business.[44] Another frequently cited
example of virus resistance mediated by gene silencing involves papaya, where the Hawaiian
papaya industry was rescued by virus-resistant GM papayas produced and licensed by university
researchers rather than a large corporation.[45] These papayas also remain in use at present,
although not without significant public protest,[46][47] which is notably less evident in medical
uses of gene silencing.
Gene silencing techniques have also been used to target other viruses, such as the human
papilloma virus, the West Nile virus, and the Tulane virus. The E6 gene in tumor samples
retrieved from patients with the human papilloma virus was targeted and found to cause
apoptosis in the infected cells.[48] Plasmid siRNA expression vectors used to target the West
Nile virus were also able to prevent the replication of viruses in cell lines.[49] In addition, siRNA
has been found to be successful in preventing the replication of the Tulane virus, part of the
virus family Caliciviridae, by targeting both its structural and non-structural genes.[50] By
targeting the NTPase gene, one dose of siRNA 4 hours pre-infection was shown to control
Tulane virus replication for 48 hours post-infection, reducing the viral titer by up to 2.6
logarithms.[50] Although the Tulane virus is species-specific and does not affect humans, it has
been shown to be closely related to the human norovirus, which is the most common cause of
acute gastroenteritis and food-borne disease outbreaks in the United States.[51] Human
noroviruses are notorious for being difficult to study in the laboratory, but the Tulane virus offers
a model through which to study this family of viruses for the clinical goal of developing therapies
that can be used to treat illnesses caused by human norovirus.
Bacteria
Structure of a typical Gram-positive bacterial cell
Unlike viruses, bacteria are not as susceptible to silencing by siRNA.[52] This is largely due to
how bacteria replicate. Bacteria replicate outside of the host cell and do not contain the
necessary machinery for RNAi to function.[52] However, bacterial infections can still be
suppressed by siRNA by targeting the host genes that are involved in the immune response
caused by the infection or by targeting the host genes involved in mediating the entry of bacteria
into cells.[52][53] For instance, siRNA was used to reduce the amount of pro-inflammatory
cytokines expressed in the cells of mice treated with lipopolysaccharide (LPS).[52][54] The
reduced expression of the inflammatory cytokine, tumor necrosis factor α (TNFα), in turn,
caused a reduction in the septic shock felt by the LPS-treated mice.[54] In addition, siRNA was
used to prevent the bacteria, Psueomonas aeruginosa, from invading murine lung epithelial cells
by knocking down the caveolin-2 (CAV2) gene.[55] Thus, though bacteria cannot be directly
targeted by siRNA mechanisms, they can still be affected by siRNA when the components
involved in the bacterial infection are targeted.
Respiratory diseases
Ribozymes, antisense oligonucleotides, and more recently RNAi have been used to target mRNA
molecules involved in asthma.[53][56] These experiments have suggested that siRNA may be used
to combat other respiratory diseases, such as chronic obstructive pulmonary disease (COPD)
and cystic fibrosis.[53] COPD is characterized by goblet cell hyperplasia and mucus
hypersecretion.[57] Mucus secretion was found to be reduced when the transforming growth
factor (TGF)-α was targeted by siRNA in NCI-H292 human airway epithelial cells.[58] In addition to
mucus hypersecretion, chronic inflammation and damaged lung tissue are characteristic of
COPD and asthma. The transforming growth factor TGF-β is thought to play a role in these
manifestations.[59][60] As a result, when interferon (IFN)-γ was used to knock down TGF-β,
fibrosis of the lungs, caused by damage and scarring to lung tissue, was improved.[61][62]
Neurodegenerative disorders
Huntington's disease
Crystallographic structure of the N-terminal region of the human huntingtin protein.
Huntington's disease (HD) results from a mutation in the huntingtin gene that causes an excess
of CAG repeats.[63] The gene then forms a mutated huntingtin protein with polyglutamine repeats
near the amino terminus.[64] This disease is incurable and known to cause motor, cognitive, and
behavioral deficits.[65] Researchers have been looking to gene silencing as a potential
therapeutic for HD.
Gene silencing can be used to treat HD by targeting the mutant huntingtin protein. The mutant
huntingtin protein has been targeted through gene silencing that is allele specific using allele
specific oligonucleotides. In this method, the antisense oligonucleotides are used to target
single nucleotide polymorphism (SNPs), which are single nucleotide changes in the DNA
sequence, since HD patients have been found to share common SNPs that are associated with
the mutated huntingtin allele. It has been found that approximately 85% of patients with HD can
be covered when three SNPs are targeted. In addition, when antisense oligonucleotides were
used to target an HD-associated SNP in mice, there was a 50% decrease in the mutant
huntingtin protein.[63]
Non-allele specific gene silencing using siRNA molecules has also been used to silence the
mutant huntingtin proteins. Through this approach, instead of targeting SNPs on the mutated
protein, all of the normal and mutated huntingtin proteins are targeted. When studied in mice, it
was found that siRNA could reduce the normal and mutant huntingtin levels by 75%. At this level,
they found that the mice developed improved motor control and a longer survival rate when
compared to the controls.[63] Thus, gene silencing methods may prove to be beneficial in treating
HD.
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a motor neuron disease
that affects the brain and spinal cord. The disease causes motor neurons to degenerate, which
eventually leads to neuron death and muscular degeneration.[66] Hundreds of mutations in the
Cu/Zn superoxide dismutase (SOD1) gene have been found to cause ALS.[67] Gene silencing has
been used to knock down the SOD1 mutant that is characteristic of ALS.[67][68] In specific, siRNA
molecules have been successfully used to target the SOD1 mutant gene and reduce its
expression through allele-specific gene silencing.[67][69]
Therapeutics challenges
Basic mechanism used by viral vectors to deliver genes to target cells. Example shown is a lentiviral vector.
There are several challenges associated with gene silencing therapies, including delivery and
specificity for targeted cells. For instance, for treatment of neurodegenerative disorders,
molecules for a prospective gene silencing therapy must be delivered to the brain. The bloodbrain barrier makes it difficult to deliver molecules into the brain through the bloodstream by
preventing the passage of the majority of molecules that are injected or absorbed into the
blood.[63][64] Thus, researchers have found that they must directly inject the molecules or implant
pumps that push them into the brain.[63]
Once inside the brain, however, the molecules must move inside of the targeted cells. In order to
efficiently deliver siRNA molecules into the cells, viral vectors can be used.[63][65] Nevertheless,
this method of delivery can also be problematic as it can elicit an immune response against the
molecules. In addition to delivery, specificity has also been found to be an issue in gene
silencing. Both antisense oligonucleotides and siRNA molecules can potentially bind to the
wrong mRNA molecule.[63] Thus, researchers are searching for more efficient methods to deliver
and develop specific gene silencing therapeutics that are still safe and effective.
Food
Arctic Apples are a suite of trademarked[70] apples that contain a nonbrowning trait created by
using gene silencing to reduce the expression of polyphenol oxidase (PPO). It is the first
approved food product to use this technique.[71]
See also
CRISPR
DNA-directed RNA interference
Gene drive
Gene knockdown
PPRHs
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Gene+silencing (https://meshb.nlm.nih.gov/record/ui?name=Gene%20silencing)
at the US
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"https://en.wikipedia.org/w/index.php?
title=Gene_silencing&oldid=1075898899"
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