Post-transcriptional regulation
Encyclopedia
Post-transcriptional regulation is the control of gene expression
at the RNA
level, therefore between the transcription
and the translation
of the gene
.
(transcriptional regulation) where due to the chromatin
arrangement and due to the activity of transcription factors, genes are differentially transcribed.
After being produced, the stability and distribution of the different transcripts is regulated (post-transcriptional regulation) by means of RNA
binding protein
(RBP) that control the various steps and rates of the transcripts: events such as alternative splicing
, nuclear degradation (exosome
), processing, nuclear export (three alternative pathways), sequestration in DCP2
-bodies for storage or degradation, and ultimately translation. These proteins achieve these events thanks to a RNA recognition motif (RRM) that binds a specific sequence or secondary structure
of the transcripts, typically at the 5’
and 3’ UTR
of the transcript.
Modulating the capping, splicing, addition of a Poly(A) tail
, the sequence-specific nuclear export rates and in several contexts sequestration of the RNA transcript occurs in eukaryotes but not in prokaryotes. This modulation is a result of a protein or transcript which in turn is regulated and may have an affinity for certain sequences.
Furthermore RNA found in the nucleus is more complex than that found in the cytoplasm: more than 95% (bases) of the RNA synthesized by RNA polymerase II
never reaches the cytoplasm
. The main reason for this is due to the removal of intron
s which account for 80% of the total bases. Some studies have shown that even after processing the levels of mRNA between the cytoplasm and the nucleus differ greatly.
Developmental biology is a good source of models of regulation, but due to the technical difficulties it was easier to determine the transcription factor cascades than regulation at the RNA level. In fact several key genes such as nanos are known to bind RNA but often their targets are unknown. Although RNA binding proteins may regulate post transcriptionally large amount of the transcriptome, the targeting of a single gene is of interest to the scientific community for medical reasons, this is RNA interference
and microRNAs which are both examples of posttranscriptional regulation, which regulate the destruction of RNA and change the chromatin structure. To study post-transcriptional regulation several techniques are used, such as RIP-Chip
(RNA immunoprecipitation
on chip).
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...
at the RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
level, therefore between the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and the translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
of the 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...
.
Mechanism
The first instance of regulation is at transcriptionTranscription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
(transcriptional regulation) where due to the chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
arrangement and due to the activity of transcription factors, genes are differentially transcribed.
After being produced, the stability and distribution of the different transcripts is regulated (post-transcriptional regulation) by means of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
binding protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
(RBP) that control the various steps and rates of the transcripts: events such as alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
, nuclear degradation (exosome
Exosome complex
The exosome complex is a multi-protein complex capable of degrading various types of RNA molecules...
), processing, nuclear export (three alternative pathways), sequestration in DCP2
DCP2
mRNA-decapping enzyme 2 is a protein that in humans is encoded by the DCP2 gene.-Interactions:DCP2 has been shown to interact with DCP1A and UPF1.-Further reading:...
-bodies for storage or degradation, and ultimately translation. These proteins achieve these events thanks to a RNA recognition motif (RRM) that binds a specific sequence or secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
of the transcripts, typically at the 5’
Five prime untranslated region
A messenger ribonucleic acid molecule codes for a protein through translation. The mRNA also contains regions that are not translated: in eukaryotes these include the 5' untranslated region, 3' untranslated region, 5' cap and poly-A tail....
and 3’ UTR
Three prime untranslated region
In molecular genetics, the three prime untranslated region is a particular section of messenger RNA . It is preceeded by the coding region....
of the transcript.
Modulating the capping, splicing, addition of a Poly(A) tail
Polyadenylation
Polyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
, the sequence-specific nuclear export rates and in several contexts sequestration of the RNA transcript occurs in eukaryotes but not in prokaryotes. This modulation is a result of a protein or transcript which in turn is regulated and may have an affinity for certain sequences.
- Capping changes the five prime end of the mRNA to a three prime end by 5'-5' linkage, which protects the mRNA from 5' exonucleaseExonucleaseExonucleases are enzymes that work by cleaving nucleotides one at a time from the end of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3’ or the 5’ end occurs. Its close relative is the endonuclease, which cleaves phosphodiester bonds in the middle ...
, which degrades foreign RNA. The cap also helps in ribosomal binding. - Splicing removes the intronIntronAn intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
s, noncoding regions that are transcribed into RNA, in order to make the mRNA able to create proteins. Cells do this by spliceosomes binding on either side of an intron, looping the intron into a circle and then cleaving it off. The two ends of the exons are then joined together. - Addition of poly(A) tail otherwise known as polyadenylationPolyadenylationPolyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
. Junk RNA is added to the 3' end, and acts as a buffer to the 3' exonuclease in order to increase the half life of mRNA. In addition, a long poly(A) tail can increase translation. Poly(A)-binding proteinPoly(A)-binding proteinPoly-binding protein is a RNA-binding protein which binds to the poly tail of mRNA. The poly tail is located on the 3' end of mRNA...
(PABP) binds to a long poly(A) tail and mediates the interaction between EIF4EEIF4EEukaryotic translation initiation factor 4E, also known as eIF4E, is a protein which in humans is encoded by the eIF4E gene.- Function :...
and EIF4GEIF4GeIF4G is a protein involved in bringing mRNA to the ribosome for translation, generally based on mRNA's distinctive guanosine cap. Species versions of eIF4G have been studied in everything from humans, to yeast, to wheat...
which encourages the initiation of translation. - RNA editing is a process which results in sequence variation in the RNA molecule, and is catalyzed by enzymes. These enzymes include the Adenosine Deaminase Acting on RNA (ADARADARDouble-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene.-Further reading:...
) enzymes, which convert specific adenosine residues to inosine in an mRNA molecule by hydrolytic deamination. Three ADAR enzymes have been cloned, ADAR1, ADAR2 and ADAR3, although only the first two subtypes have been shown to have RNA editing activity. Many mRNAs are vulnerable to the effects of RNA editing, including the glutamate receptor subunits GluR2, GluR3, GluR4, GluR5 and GluR6 (which are components of the AMPA and kainate receptors), the serotonin2C receptor, the GABA-alpha3 receptor subunit, the tryptophan hydroxlase enzyme TPH2, the hepatitis delta virus and more than 16% of microRNAs. In addition to ADAR enzymes, CDAR enzymes exist and these convert cytosines in specific RNA molecules, to uracil. These enzymes are termed 'APOBEC' and have genetic loci at 22q13, a region close to the chromosomal deletion which occurs in velocardiofacial syndrome (22q11) and which is linked to psychosis. RNA editing is extensively studied in relation to infectious diseases, because the editing process alters viral function.
Significance
This area of study has recently gained more importance due to the increasing evidence that post-transcriptional regulation plays a larger role than previously expected. Even though protein with DNA binding domains are more abundant than protein with RNA binding domains*, a recent study by Cheadle et al. (2005) showed that during T-cell activation 55% of significant changes at the steady-state level had no corresponding changes at the transcriptional level, meaning they were a result of stability regulation alone.Furthermore RNA found in the nucleus is more complex than that found in the cytoplasm: more than 95% (bases) of the RNA synthesized by RNA polymerase II
RNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
never reaches the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. The main reason for this is due to the removal of intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
s which account for 80% of the total bases. Some studies have shown that even after processing the levels of mRNA between the cytoplasm and the nucleus differ greatly.
Developmental biology is a good source of models of regulation, but due to the technical difficulties it was easier to determine the transcription factor cascades than regulation at the RNA level. In fact several key genes such as nanos are known to bind RNA but often their targets are unknown. Although RNA binding proteins may regulate post transcriptionally large amount of the transcriptome, the targeting of a single gene is of interest to the scientific community for medical reasons, this is RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
and microRNAs which are both examples of posttranscriptional regulation, which regulate the destruction of RNA and change the chromatin structure. To study post-transcriptional regulation several techniques are used, such as RIP-Chip
RIP-Chip
RIP-Chip is immunoprecipitation of an RNA-binding protein coupled to reverse transcription and a microarray. It has been used to find interactions between RNA and protein ....
(RNA immunoprecipitation
Immunoprecipitation
Immunoprecipitation is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins...
on chip).
See also
- RiboswitchRiboswitchIn molecular biology, a riboswitch is a part of an mRNA molecule that can directly bind a small target molecule, and whose binding of the target affects the gene's activity. Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, in response to the...
- microRNA
- Glossary of gene expression termsGlossary of gene expression termsSee also: gene expression, List of Glossaries, List of Natural Sciences Glossaries-A:*Activator - protein that binds to an enhancer and activates transcription from nearby promoter....
- Wormbook.org on RNA-binding protein