Gene Silening

8/10/2019 Gene Silening

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GENE SILENCING

By: Sajjad Ahmad

PML02141003


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Definition

Gene silencingis a general term used todescribe the epigenetic regulation of geneexpression.

In particular, this term refers to the abilityof a cell to prevent the expression of acertain gene.


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Cellular components

Histones

Chromatin and heterochromatin

miRNA siRNA

dsRNA

Dicer

Transposons


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Gene silencing can occur during either

transcriptionor translation.

Often used in research. (To producetherapeutics)


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Do not confuse gene silencing with geneknockout.


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In gene silencingthe expression of agene or genes are reduced.

Whereas

In gene knockout the whole gene iseradicated from the genome therebyhaving no expression at all.


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Types of gene silencing


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1. Transcriptional gene silencing.

Includes:

Paramutation.

Transposon silencing.

Position effect.


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2. Post transcriptional gene silencing.

Includes:

RNA interference.

Nonsense mediated decay.

3.Meiotic gene silencing

Transvection


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1. Transcriptional Gene Silencing

Result from histone modifications or DNA

methylation creating an environment of

heterochromatin around a gene that makes

it inaccessible to transcriptional machinery

(RNA polymerase, transcription factors,

etc.).


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Paramutation:

Aparamutationis an interaction betweentwo allelesat a single locus, whereby one

allele induces a heritable change in the otherallele.

The allele inducing the change is said to beparamutagenic, whilst the allele that hasbeen epigenetically altered is termedparamutant(or paramutated).


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contd:

A paramutant allele may have altered levels of geneexpression,

May continue in offspring which inherit that allele, eventhough the paramutagenic allele may no longer bepresent.

Occurs mostly in plants.

Through proper breeding, paramutation can result insibling plants that have the same genetic sequence, butwith drastically different phenotypes.


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Transposon silencing.

A Transposon is a DNA sequence that can change its

position within the genome, sometimes creating orreversing mutations and altering the cell's genome size.

Transposition often results in duplication of the TE.

Barbara McClintock's discovery of thesejumpinggenesearned her a Nobel prize in 1983.


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Contd:

Transposon silencing is a form of transcriptionalgene silencing targeting transposons.

The jumping of transposons have the tendency togenerate genomic instability and can causeextremely deleterious mutations.

Transposable element insertions have been linked tomany diseases including hemophilia, severecombined immunodeficiency etc.


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Contd:

Silencing of transposons is therefore veryimportant in the germ line in order to stoptransposon mutations from developing and

passing on to next generations.

Studies show that siRNA play a major rolein silencing of transposons.


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Position effect:

Position effectis the effect on the expression ofa gene when its location in a chromosome is changed,

often by translocation.

This has been well described in Drosophila with respectto eye color and is known as position effectvariegation (PEV)


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Post-transcriptional gene silencing

Post-transcriptional gene silencing is the result of

mRNA of a particular gene being destroyed or blocked.

The destruction of the mRNA prevents translation to

form an active gene product in most cases, a protein.

A common mechanism of post-transcriptional gene

silencing is RNAi.


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RNA interference

The phenomenon of inhibition of gene expression by

RNA molecules is calledRNA interference (RNAi)

RNAi is caused by small interfering RNAs (siRNAs)


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RNA interference:

RNA interference (RNAi) is a natural process usedby cells to regulate gene expression.

discovered in 1998 by Andrew Fire and Craig Mello,who won the Nobel Prize for their discovery in2006.


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The process to silence genes first begins with the entranceof a double-stranded RNA (dsRNA) molecule into the cell.

This triggers the RNAi pathway.

The double-stranded molecule is then cut into smalldouble-stranded fragments by an enzyme calledDicer.

These small fragments, which include small interferingRNAs (siRNA) and microRNA (miRNA), areapproximately 21-23 nucleotides in length.


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The fragments integrate into a multi-subunitprotein called the RNAi induced silencing complex(RISC), which containsArgonauteproteins that

are essential components of the RNAi pathway.

There are 2 strands of the fragment (guide strand)and (Passenger strand).

The guide strand binds to RISC whereas

The passenger strand is degraded.


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The guide strand of the fragment remains bound toRISC and directs the sequence-specific silencing ofthe target mRNA molecule.

siRNA molecules have the ability to silence genesbye causing the endonucleatic cleavage of the targetmRNA molecules.

miRNA molecules have the ability to suppresstranslation of the mRNA molecule.


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RNAi is thought to have evolved as a cellulardefense mechanism against invaders, suchas RNA viruses, or to combat the proliferationof transposons within a cellsDNA.


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RNA Interference


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Meiotic gene silencing

Transvection:

Epigenetic phenomenon, results from aninteraction between an allele on one chromosomeand the corresponding allele on the homologouschromosome.

Transvection can lead to either gene activation or

repression. Formally, it can also occur between non allelic

regions of the genome as well as regions of thegenome that are not transcribed.


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Nonsense-mediated mRNA decay

(NMD)

Its main function is to reduce errors ingene expression by eliminating mRNA

transcripts that contain premature stopcodon.

If these aberrant mRNA transcripts weretranslated, the result would be deleteriousgain-of-function or dominant-negativeactivity of the resulting proteins.


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Applications:

Gene silencing techniques have been widely used byresearchers to study genes associated with

disorders. These disorders include:

cancer,

infectious diseases,

respiratory diseases,

and neurodegenerative disorders.


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Thank you

Documents

Gene Silening