Post-transcriptional regulation is the control of gene expression at the RNA level, therefore between the transcription and the translation of the gene.[1][2]
Contents
- 1 Mechanism
- 2 microRNA mediated regulation
- 3 Significance
- 4 microRNA role in cancer
- 5 See also
- 6 References
Mechanism
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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 P-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.
- Capping changes the five prime end of the mRNA to a three prime end by 5'-5' linkage, which protects the mRNA from 5' exonuclease, which degrades foreign RNA. The cap also helps in ribosomal binding.
- Splicing removes the introns, 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 polyadenylation. That is, a stretch of RNA that is made solely of adenine bases 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 protein (PABP) binds to a long poly(A) tail and mediates the interaction between EIF4E and EIF4G 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 (ADAR) 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.
- mRNA Stability can be manipulated in order to control its half-life, and the poly(A) tail has some effect on this stability, as previously stated. Stable mRNA can have a half life of up to a day or more which allows for the production of more protein product; unstable mRNA is used in regulation that must occur quickly.
microRNA mediated regulation
MicroRNAs (miRNAs) appear to regulate the expression of more than 60% of protein coding genes of the human genome.[3] As reviewed by Farazi et al.,[4] if an miRNA is abundant it can behave as a “switch,” turning some genes on or off. However, altered expression of many miRNAs only leads to a modest 1.5- to 4-fold change in protein expression of their target genes.[4] Individual miRNAs often repress several hundred target genes.[3][5] Repression usually occurs either through translational silencing of the mRNA or through degradation of the mRNA, via complementary binding, mostly to specific sequences in the 3' untranslated region of the target gene's mRNA.[6] The mechanism of translational silencing or degradation of mRNA is implemented through the RNA-induced silencing complex (RISC).
Significance
A prokaryotic example:
Salmonella enterica (a pathogenic γ-proteobacterium) can express two alternative porins depending on the external environment (gut or murky water), this system involves EnvZ (osomotic sensor) which activates OmpR (transcription factor) which can bind to a high affinity promoter even at low concentrations and the low affinity promoter only at high concentrations (by definition): when the concentration of this transcription factor is high it activates OmpC and micF and inhibits OmpF, OmpF is further inhibited post-transcriptionally by micF RNA which binds to the OmpF transcript
[7]
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.[8]
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 introns which account for 80% of the total bases.[9] Some studies have shown that even after processing the levels of mRNA between the cytoplasm and the nucleus differ greatly.[10]
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.[11] 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).[12]
microRNA role in cancer
Deficiency of expression of a DNA repair gene occurs in many cancers (see DNA repair defect and cancer risk and DNA repair epigenetics in cancer). Altered microRNA (miRNA) expression that either decreases accurate DNA repair or increases inaccurate microhomology-mediated end joining (MMEJ) DNA repair is often observed in cancers. Deficiency of accurate DNA repair may be a major source of the high frequency of mutations in cancer (see mutation frequencies in cancers). Repression of DNA repair genes in cancers by changes in the levels of microRNAs may be a more frequent cause of repression than mutation or epigenetic methylation of DNA repair genes.
For instance, BRCA1 is employed in the accurate homologous recombinational repair (HR) pathway. Deficiency of BRCA1 can cause breast cancer.[13] Down-regulation of BRCA1 due to mutation occurs in about 3% of breast cancers.[14] Down-regulation of BRCA1 due to methylation of its promoter occurs in about 14% of breast cancers.[15] However, increased expression of miR-182 down-regulates BRCA1 mRNA and protein expression,[16] and increased miR-182 is found in 80% of breast cancers.[17]
In another example, a mutated constitutively (persistently) expressed version of the oncogene c-Myc is found in many cancers. Among many functions, c-Myc negatively regulates microRNAs miR-150 and miR-22. These microRNAs normally repress expression of two genes essential for MMEJ, Lig3 and Parp1, thereby inhibiting this inaccurate, mutagenic DNA repair pathway. Muvarak et al.[18] showed, in leukemias, that constitutive expression of c-Myc, leading to down-regulation of miR-150 and miR-22, allowed increased expression of Lig3 and Parp1. This generates genomic instability through increased inaccurate MMEJ DNA repair, and likely contributes to progression to leukemia.
To show the frequent ability of microRNAs to alter DNA repair expression, Hatano et al.[19] performed a large screening study, in which 810 microRNAs were transfected into cells that were then subjected to ionizing radiation (IR). For 324 of these microRNAs, DNA repair was reduced (cells were killed more efficiently by IR) after transfection. For a further 75 microRNAs, DNA repair was increased, with less cell death after IR. This indicates that alterations in microRNAs may often down-regulate DNA repair, a likely important early step in progression to cancer.
See also
- RNA interference
- Cis-regulatory element
- Glossary of gene expression terms
- Wormbook.org on RNA-binding protein
References
- ^ Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter (2007). Molecular Biology of the Cell (Fifth ed.). Garland Science. pp. 1268 pages. ISBN 0-8153-4105-9.
- ^ Weaver, Robert J. (2007). "Part V: Post-transcriptional events". Molecular Biology. Boston: McGraw Hill Higher Education. ISBN 0-07-110216-7.
- ^ a b Friedman RC, Farh KK, Burge CB, Bartel DP (2009). "Most mammalian mRNAs are conserved targets of microRNAs". Genome Res. 19 (1): 92–105. doi:10.1101/gr.082701.108. PMC 2612969. PMID 18955434.
- ^ a b Farazi TA, Spitzer JI, Morozov P, Tuschl T (2011). "miRNAs in human cancer". J. Pathol. 223 (2): 102–15. doi:10.1002/path.2806. PMC 3069496. PMID 21125669.
- ^ Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (2005). "Microarray analysis shows that some microRNAs downregulate large numbers of the target mRNAs". Nature 433 (7027): 769–73. doi:10.1038/nature03315. PMID 15685193.
- ^ Hu W, Coller J (2012). "What comes first: translational repression or mRNA degradation? The deepening mystery of microRNA function". Cell Res. 22 (9): 1322–4. doi:10.1038/cr.2012.80. PMC 3434348. PMID 22613951.
- ^ Mims C, Nash A, Stephen J. Mims' pathogenesis of infectious disease. 2001. 5th. Academic press. ISBN 0-12-498264-6
- ^ Cheadle C, Fan J, Cho-Chung YS, Werner T, Ray J, Do L, Gorospe M, Becker KG (2005). "Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability". BMC Genomics 6: 75. doi:10.1186/1471-2164-6-75. PMC 1156890. PMID 15907206.
- ^ Jackson DA, Pombo A, Iborra F (2000). "The balance sheet for transcription: an analysis of nuclear RNA metabolism in mammalian cells". FASEB J. 14 (2): 242–54. PMID 10657981.
- ^ Schwanekamp JA, Sartor MA, Karyala S, Halbleib D, Medvedovic M, Tomlinson CR (2006). "Genome-wide analyses show that nuclear and cytoplasmic RNA levels are differentially affected by dioxin". Biochim. Biophys. Acta 1759 (8–9): 388–402. doi:10.1016/j.bbaexp.2006.07.005. PMID 16962184.
- ^ Scott F. Gilbert. Developmental Biology. Sinauer, 2003. ISBN 0-87893-258-5.
- ^ Keene JD, Komisarow JM, Friedersdorf MB (2006). "RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts". Nat Protoc 1 (1): 302–7. doi:10.1038/nprot.2006.47. PMID 17406249.
- ^ Magdinier F, Ribieras S, Lenoir GM, Frappart L, Dante R (1998). "Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region". Oncogene 17 (24): 3169–76. doi:10.1038/sj.onc.1202248. PMID 9872332.
- ^ Whittemore AS, Gong G, Itnyre J (1997). "Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer". Am. J. Hum. Genet. 60 (3): 496–504. PMC 1712497. PMID 9042908.
- ^ Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW (2000). "Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens". Carcinogenesis 21 (9): 1761–5. PMID 10964110.
- ^ Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D (2011). "miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors". Mol. Cell 41 (2): 210–20. doi:10.1016/j.molcel.2010.12.005. PMC 3249932. PMID 21195000.
- ^ Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM (2013). "MicroRNA-182-5p targets a network of genes involved in DNA repair". RNA 19 (2): 230–42. doi:10.1261/rna.034926.112. PMC 3543090. PMID 23249749.
- ^ Muvarak N, Kelley S, Robert C, Baer MR, Perrotti D, Gambacorti-Passerini C, Civin C, Scheibner K, Rassool FV (2015). "c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias". Mol. Cancer Res. 13 (4): 699–712. doi:10.1158/1541-7786.MCR-14-0422. PMID 25828893.
- ^ Hatano K, Kumar B, Zhang Y, Coulter JB, Hedayati M, Mears B, Ni X, Kudrolli TA, Chowdhury WH, Rodriguez R, DeWeese TL, Lupold SE (2015). "A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation". Nucleic Acids Res. 43 (8): 4075–86. doi:10.1093/nar/gkv273. PMID 25845598.
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Gene expression
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Introduction
to genetics |
- Genetic code
- Central dogma
- Special transfers
- RNA→RNA
- RNA→DNA
- Protein→Protein
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| Transcription |
| Types |
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| Key elements |
- Transcription factor
- RNA polymerase
- Promoter
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| Post-transcription |
- Precursor mRNA (pre-mRNA / hnRNA)
- 5' capping
- Splicing
- Polyadenylation
- Histone acetylation and deacetylation
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| Translation |
| Types |
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| Key elements |
- Ribosome
- Transfer RNA (tRNA)
- Ribosome-nascent chain complex (RNC)
- Post-translational modification (functional groups · peptides · structural changes)
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| Regulation |
- Epigenetic
- Transcriptional
- Post-transcriptional
- sequestration (P-bodies)
- alternative splicing
- microRNA
- Translational
- Post-translational
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Index of genetics
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| Description |
- Gene expression
- DNA
- replication
- cycle
- recombination
- repair
- binding proteins
- Transcription
- factors
- regulators
- nucleic acids
- RNA
- RNA binding proteins
- ribonucleoproteins
- repeated sequence
- modification
- Translation
- ribosome
- modification
- nexins
- Proteins
- domains
- Structure
- primary
- secondary
- tertiary
- quaternary
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| Disease |
- Replication and repair
- Transcription factor
- Transcription
- Translation
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Molecular biology
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- Computational biology
- Developmental biology
- Functional biology/medicine
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| Overview |
| Central dogma |
- History of molecular biology
- DNA replication (DNA)
- Transcription (RNA)
- Translation (protein)
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| Element |
- Promoter
- Operon
- gal operon
- lac operon
- trp operon
- Intron
- Exon
- Terminator
- Enhancer
- Repressor
- lac repressor
- trp repressor
- Silencer
- Histone methylation
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| Linked life |
- Cell biology
- Biochemistry
- Computational biology
- Genetics
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| Engineering |
| Concepts |
- Mitosis
- Cell signalling
- Post-transcriptional modification
- Post-translational modification
- Dry lab / Wet lab
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| Techniques |
- Cell culture
- Model organisms (such as C57BL/6 mice)
- Methods
- Fluorescence, Pigment & Radioactivity
- High-throughput technique ("-omics")
- DNA microarray
- Mass spectrometry
- Lab-on-a-chip
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| Gene regulation |
- Epigenetic
- Genetic
- Post-transcriptional
- Post-translational regulation
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- Glossary
- Molecular biology
- Molecular and cellular biology
- WikiProject
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|
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Gene expression
|
|
Introduction
to genetics |
- Genetic code
- Central dogma
- Special transfers
- RNA→RNA
- RNA→DNA
- Protein→Protein
|
|
| Transcription |
| Types |
|
|
| Key elements |
- Transcription factor
- RNA polymerase
- Promoter
|
|
| Post-transcription |
- Precursor mRNA (pre-mRNA / hnRNA)
- 5' capping
- Splicing
- Polyadenylation
- Histone acetylation and deacetylation
|
|
|
| Translation |
| Types |
|
|
| Key elements |
- Ribosome
- Transfer RNA (tRNA)
- Ribosome-nascent chain complex (RNC)
- Post-translational modification (functional groups · peptides · structural changes)
|
|
|
| Regulation |
- Epigenetic
- Transcriptional
- Post-transcriptional
- sequestration (P-bodies)
- alternative splicing
- microRNA
- Translational
- Post-translational
|
|
|
Index of genetics
|
|
| Description |
- Gene expression
- DNA
- replication
- cycle
- recombination
- repair
- binding proteins
- Transcription
- factors
- regulators
- nucleic acids
- RNA
- RNA binding proteins
- ribonucleoproteins
- repeated sequence
- modification
- Translation
- ribosome
- modification
- nexins
- Proteins
- domains
- Structure
- primary
- secondary
- tertiary
- quaternary
|
|
| Disease |
- Replication and repair
- Transcription factor
- Transcription
- Translation
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Transcription (Bacterial, Eukaryotic)
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| Transcriptional regulation |
| prokaryotic |
- Operon
- lac operon
- trp operon
- gab operon
- ara operon
- gal operon
- Repressor
- lac repressor
- trp repressor
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| eukaryotic |
Histone-modifying enzymes
(histone/nucleosome): |
- Histone methylation/Histone methyltransferase
- Histone demethylase
- Histone acetylation and deacetylation
- Histone deacetylase HDAC1
- Histone acetyltransferase
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| DNA methylation: |
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| Chromatin remodeling: |
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| both |
- Transcription coregulator
- Inducer
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| Promotion |
- Promoter
- Pribnow box
- TATA box
- BRE
- CAAT box
- Response element
- Enhancer
- Insulator
- Silencer
- Internal control region
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Initiation (bacterial,
eukaryotic |
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| Elongation |
- bacterial RNA polymerase: rpoB
- eukaryotic RNA polymerase: RNA polymerase II
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Termination
(bacterial,
eukaryotic) |
- Terminator
- Intrinsic termination
- Rho factor
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Index of genetics
|
|
| Description |
- Gene expression
- DNA
- replication
- cycle
- recombination
- repair
- binding proteins
- Transcription
- factors
- regulators
- nucleic acids
- RNA
- RNA binding proteins
- ribonucleoproteins
- repeated sequence
- modification
- Translation
- ribosome
- modification
- nexins
- Proteins
- domains
- Structure
- primary
- secondary
- tertiary
- quaternary
|
|
| Disease |
- Replication and repair
- Transcription factor
- Transcription
- Translation
|
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