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11.2: Post-Transcriptional Regulation - Biology

11.2: Post-Transcriptional Regulation - Biology


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Basics of Protein Translation

For the basics of transcription and translation, refer to Lecture 1, sections 4.3 - 4.5.

The genetic code is almost universal.

FAQ

Q: Why is genetic code so similar across organisms?

A: Genomic material is not only transmitted vertically (from parents) but also horizontally between organisms. This gene interaction creates an evolutionary pressure for an universal genetic code.

FAQ

Q: What accounts for the slight differences in the genetic code across organisms?

A: Late/early evolutionary arrival of amino acids can account for the differences. Also, certain species (e.g. bacteria in deep sea vents) have more resources to synthesize specific amino acids, thus they will favor those in the genetic code.

Did You Know?

Threonine and Alanine are often accidentally interchanged by tRNA sythetase because they originated from one amino acid.

Measuring Translation

Translation efficiency is defined as,

[T_{e f f}=frac{[mathrm{mRNA}]}{[mathrm{protein}]} onumber]

We are interested in seeing just how much of our mRNA is translated to protein, i.e. the efficiency. However, specifically measuring how much mRNA becomes protein is a difficult task, one that requires a bit of creativity. There are a variety of ways to tackle this problem, but each has its own downfalls:

1. Measure mRNA and protein levels directly
Pitfall: Does not consider rates of synthesis and degradation. This method measures the protein levels for the ’old’ mRNA since there is a time lag from mRNA to protein.

2. Use drugs to inhibit transcription and translation Pitfall: Drugs have side effects altering translation

3. Artificial fusion of proteins with tags
Pitfall: Protein tags can affect protein stability

4. Pulse label with radioactive nucleosides or amino acids (SILAC) **in use today**

Pitfall: Offers no information on dynamic changes: it is simply a snapshat of the resulting mRNA and protein levels after X hours 193

Another common technique is using ’ribosome profiling’ to measure protein translation at subcodon res- olution. This is done by freezing ribosomes in the process of translation and degrading the non-ribosome protected sequences. At this point, the sequences can be pieced back together and the frequency with which a region is translated can be interpolated. The disadvantage to using these ribosome footprints, to see which regions are being translated, is that regions in between ribosomes are lost. This technique requires an RNA-seq in parallel.

The question remains, why is Ribosome profiling advantageous? This technique is a better approach to measuring protein abundance as it:

1. Is a better measure of protein abundance
2. Is independent of protein degradation (compared to the protein abundance/mRNA ratio)

3. Allows us to measure codon-specific translation rates

Using ribosome profiling, it is possible to see which codon is being decoded: this is done by mapping ribosome footprints and then deciphering the translating codon based on footprint length. We can the verify our prediction by mapping translated codon profiles based on periodicity (three bases in a codon). The technique can be improved even further by using anti-translation drugs such as harringtonine and cyclohexamide. Cyclohexamide blocks elongation and Harringtonine inhibits initiation. The later can be used to find the starting points (which genes are about to be translated). Figure 4 shows the effects of the drugs on the ribosome profiles.

This technique has much more to offer than simply quantifying translation. Ribosome profiling allows for:

1. Prediction of alternative isoforms (different places where translation can start) images/AltIsoforms.png

2. Prediction of un-indentified ORFs (open reading frames)

Figure 11.6: Ribosome profile when harringtonine is used vs. no drug. The red peaks previously un-identified ORFs.

3. Comparing translation across different environmental conditions

4. Comparing translation across life stages

Thus, we see that ribosome profiling is a very powerful tool with lots of potential to reveal previously elusive information about the translation of a genome.

Codon Evolution

Basic concepts

Something to make clear is that codons are not used with equal frequencies. In fact, which codons can be considered optimal differs across different species based on RNA stability, strand-specific mutation bias, transcriptional efficacy, GC composition, protein hydropathy, and translational efficiency. Likewise, tRNA isoacceptors are not used with equal frequencies within and across species. The motivation for the next section is to determine how we may measure this codon bias.

Measures of Codon Bias

There are a few methods to accomplish this task:

a) Calculate the frequency of optimal codons, which is defined as “optimal” codons/ sum of “optimal” and “non-optimal” codons. The limitations to this method are that this requires knowing which codon is recognized by each tRNA and it assumes that tRNA abundance is highly correlated with tRNA gene copy number.

b) Calculate a codon bias index. This measures the rate of optimal codons with respect to the total codons encoding for that same amino acid. However, in this case the number of optimal codons are normalized with respect to the expected random usage. CBI = (oopt − erand)/(otot − erand). The limitation of this method is that it requires a reference set of proteins, such as highly expressed ribosomal proteins.

c) Calculate a codon adaptation index. This measures the relative adaptiveness or deviation of the codon us- age of a gene towards the codon usage of a reference set of proteins, i.e. highly expressed genes. It is defined as the geometric mean of the relative adaptiveness values, measured as weights associated to each codon over the length of the gene sequence (measured in codons). Each weight is computed as the ratio between the observed frequency of a given codon and the frequency of its corresponding amino acid. The limita- tion to this approach is that it requires the definition of a reference set of proteins, just as the last method did.

d) Calculate the effective number of codons. This measures the total number of different codons used in a sequence, which measures the bias toward the use of a smaller subset of codons, away from equal use of synonymous codons. Nc = 20 if only one codon is used per amino acid, and Nc = 61 when all possible synonymous codons are used equally. The steps to the process are to compute the homozygosity for each amino acid as estimated from the squared codon frequencies, obtain effective number of codons per amino acid, and compute the overall number of effective codons. This method is advantageous because it does not require any knowledge of tRNA-codon pairing, and it does not require any reference set However, it is limited in that it does not take into account the tRNA pool.

e) Calculate the tRNA adaptation index. Assume that tRNA gene copy number has a high positive correla- tion with tRNA abundance within the cell. This then measures how well a gene is adapted to the tRNA pool.

It is important to distinguish among when to use each index. The situation in which a certain index is favorable is very context-based, and thus it is often preferable to use one index above all others when the situation calls for it. By carefully choosing an index, one can uncover information about the frequency by which a codon is translated to an amino acid.

RNA Modifications

The story becomes more complicated when we consider modifications that can occur to RNA. For instance, some modifications can expand or restrict the wobbling capacity of the tRNA. Examples include insosine modifications and xo5U modifications. These modifications allow tRNAs to decode a codon that they could not read before. One might ask why RNA modification was positively selected in the context of evolution, and the rationale is that this allows for the increase in the probability that a matching tRNA exists to decode a codon in a given environment.

Examples of applications

There are a few natural applications that result form our understanding of codon evolution.

a) Codon optimization for heterologous protein expression
b) Predicting coding and non-coding regions of a genome
c) Predicting codon read-through
d) Understanding how genes are decoded - studying patterns of codon usage bias along genes

Translational Regulation

There are many known means of regulation at the post-transcriptional level. These include modulation of tRNA availability, changes in mRNA, and cis -and trans-regulatory elements. First, tRNA modulation has a large impact. Changes in tRNA isoacceptors, changes in tRNA modifications, and regulation at tRNA aminoacylation levels. Changes in mRNA that affect translation include changes in mRNA modification, polyA tail, splicing, capping, and the localization of mRNA (importing to and exporting from nucleus). Cis- and trans- regulatory elements include RNA interference (i.e. siRNA and miRNA), frameshift events, and riboswitches. Additionally, many regulatory elements are still yet to be discovered!


11.2: Post-Transcriptional Regulation - Biology

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POSTAR2: deciphering the post-transcriptional regulatory logics

Post-transcriptional regulation of RNAs is critical to the diverse range of cellular processes. The volume of functional genomic data focusing on post-transcriptional regulation logics continues to grow in recent years. In the current database version, POSTAR2 (http://lulab.life.tsinghua.edu.cn/postar), we included the following new features and data: updated ∼500 CLIP-seq datasets (∼1200 CLIP-seq datasets in total) from six species, including human, mouse, fly, worm, Arabidopsis and yeast added a new module 'Translatome', which is derived from Ribo-seq datasets and contains ∼36 million open reading frames (ORFs) in the genomes from the six species updated and unified post-transcriptional regulation and variation data. Finally, we improved web interfaces for searching and visualizing protein-RNA interactions with multi-layer information. Meanwhile, we also merged our CLIPdb database into POSTAR2. POSTAR2 will help researchers investigate the post-transcriptional regulatory logics coordinated by RNA-binding proteins and translational landscape of cellular RNAs.

Figures

Framework to construct POSTAR2 database.…

Framework to construct POSTAR2 database. ( A ) POSTAR2 covers six species including…

Statistics of POSTAR2 database. (…

Statistics of POSTAR2 database. ( A ) Number of RBPs in the human,…

Integrative viewing of translation activity…

Integrative viewing of translation activity of a target gene (ADAM17) and its post-transcriptionally…


The emerging biology of RNA post-transcriptional modifications

RNA modifications have long been known to be central in the proper function of tRNA and rRNA. While chemical modifications in mRNA were discovered decades ago, their function has remained largely mysterious until recently. Using enrichment strategies coupled to next generation sequencing, multiple modifications have now been mapped on a transcriptome-wide scale in a variety of contexts. We now know that RNA modifications influence cell biology by many different mechanisms - by influencing RNA structure, by tuning interactions within the ribosome, and by recruiting specific binding proteins that intersect with other signaling pathways. They are also dynamic, changing in distribution or level in response to stresses such as heat shock and nutrient deprivation. Here, we provide an overview of recent themes that have emerged from the substantial progress that has been made in our understanding of chemical modifications across many major RNA classes in eukaryotes.

Keywords: Epitranscriptome RNA modification gene expression post-transcriptional regulation protein translation.

Figures

Chemical structures of RNA modifications…

Chemical structures of RNA modifications currently characterized in mRNA, schematized with their reported…


83 Eukaryotic Post-transcriptional Gene Regulation

By the end of this section, you will be able to do the following:

  • Understand RNA splicing and explain its role in regulating gene expression
  • Describe the importance of RNA stability in gene regulation

RNA is transcribed, but must be processed into a mature form before translation can begin. This processing that takes place after an RNA molecule has been transcribed, but before it is translated into a protein, is called post-transcriptional modification. As with the epigenetic and transcriptional stages of processing, this post-transcriptional step can also be regulated to control gene expression in the cell. If the RNA is not processed, shuttled, or translated, then no protein will be synthesized.

RNA Splicing, the First Stage of Post-transcriptional Control

In eukaryotic cells, the RNA transcript often contains regions, called introns, that are removed prior to translation. The regions of RNA that code for protein are called exons . ((Figure)). After an RNA molecule has been transcribed, but prior to its departure from the nucleus to be translated, the RNA is processed and the introns are removed by splicing. Splicing is done by spliceosomes, ribonucleoprotein complexes that can recognize the two ends of the intron, cut the transcript at those two points, and bring the exons together for ligation.


Alternative RNA Splicing In the 1970s, genes were first observed that exhibited alternative RNA splicing. Alternative RNA splicing is a mechanism that allows different protein products to be produced from one gene when different combinations of exons are combined to form the mRNA ((Figure)). This alternative splicing can be haphazard, but more often it is controlled and acts as a mechanism of gene regulation, with the frequency of different splicing alternatives controlled by the cell as a way to control the production of different protein products in different cells or at different stages of development. Alternative splicing is now understood to be a common mechanism of gene regulation in eukaryotes according to one estimate, 70 percent of genes in humans are expressed as multiple proteins through alternative splicing. Although there are multiple ways to alternatively splice RNA transcripts, the original 5′-3′ order of the exons is always conserved. That is, a transcript with exons 1 2 3 4 5 6 7 might be spliced 1 2 4 5 6 7 or 1 2 3 6 7, but never 1 2 5 4 3 6 7.


How could alternative splicing evolve? Introns have a beginning- and ending-recognition sequence it is easy to imagine the failure of the splicing mechanism to identify the end of an intron and instead find the end of the next intron, thus removing two introns and the intervening exon. In fact, there are mechanisms in place to prevent such intron skipping, but mutations are likely to lead to their failure. Such “mistakes” would more than likely produce a nonfunctional protein. Indeed, the cause of many genetic diseases is abnormal splicing rather than mutations in a coding sequence. However, alternative splicing could possibly create a protein variant without the loss of the original protein, opening up possibilities for adaptation of the new variant to new functions. Gene duplication has played an important role in the evolution of new functions in a similar way by providing genes that may evolve without eliminating the original, functional protein.

Question: In the corn snake Pantherophis guttatus, there are several different color variants, including amelanistic snakes whose skin patterns display only red and yellow pigments. The cause of amelanism in these snakes was recently identified as the insertion of a transposable element into an intron in the OCA2 (oculocutaneous albinism) gene. How might the insertion of extra genetic material into an intron lead to a nonfunctional protein?

Visualize how mRNA splicing happens by watching the process in action in this video.

Control of RNA Stability

Before the mRNA leaves the nucleus, it is given two protective “caps” that prevent the ends of the strand from degrading during its journey. 5′ and 3′ exonucleases can degrade unprotected RNAs. The 5′ cap , which is placed on the 5′ end of the mRNA, is usually composed of a methylated guanosine triphosphate molecule (GTP). The GTP is placed “backward” on the 5′ end of the mRNA, so that the 5′ carbons of the GTP and the terminal nucleotide are linked through three phosphates. The poly-A tail , which is attached to the 3′ end, is usually composed of a long chain of adenine nucleotides. These changes protect the two ends of the RNA from exonuclease attack.

Once the RNA is transported to the cytoplasm, the length of time that the RNA resides there can be controlled. Each RNA molecule has a defined lifespan and decays at a specific rate. This rate of decay can influence how much protein is in the cell. If the decay rate is increased, the RNA will not exist in the cytoplasm as long, shortening the time available for translation of the mRNA to occur. Conversely, if the rate of decay is decreased, the mRNA molecule will reside in the cytoplasm longer and more protein can be translated. This rate of decay is referred to as the RNA stability. If the RNA is stable, it will be detected for longer periods of time in the cytoplasm.

Binding of proteins to the RNA can also influence its stability. Proteins called RNA-binding proteins , or RBPs, can bind to the regions of the mRNA just upstream or downstream of the protein-coding region. These regions in the RNA that are not translated into protein are called the untranslated regions , or UTRs. They are not introns (those have been removed in the nucleus). Rather, these are regions that regulate mRNA localization, stability, and protein translation. The region just before the protein-coding region is called the 5′ UTR , whereas the region after the coding region is called the 3′ UTR ((Figure)). The binding of RBPs to these regions can increase or decrease the stability of an RNA molecule, depending on the specific RBP that binds.


RNA Stability and microRNAs

In addition to RBPs that bind to and control (increase or decrease) RNA stability, other elements called microRNAs can bind to the RNA molecule. These microRNAs , or miRNAs, are short RNA molecules that are only 21 to 24 nucleotides in length. The miRNAs are made in the nucleus as longer pre-miRNAs. These pre-miRNAs are chopped into mature miRNAs by a protein called Dicer . Like transcription factors and RBPs, mature miRNAs recognize a specific sequence and bind to the RNA however, miRNAs also associate with a ribonucleoprotein complex called the RNA-induced silencing complex (RISC) . The RNA component of the RISC base-pairs with complementary sequences on an mRNA and either impede translation of the message or lead to the degradation of the mRNA.

Section Summary

Post-transcriptional control can occur at any stage after transcription, including RNA splicing and RNA stability. Once RNA is transcribed, it must be processed to create a mature RNA that is ready to be translated. This involves the removal of introns that do not code for protein. Spliceosomes bind to the signals that mark the exon/intron border to remove the introns and ligate the exons together. Once this occurs, the RNA is mature and can be translated. Alternative splicing can produce more than one mRNA from a given transcript. Different splicing variants may be produced under different conditions.

RNA is created and spliced in the nucleus, but needs to be transported to the cytoplasm to be translated. RNA is transported to the cytoplasm through the nuclear pore complex. Once the RNA is in the cytoplasm, the length of time it resides there before being degraded, called RNA stability, can also be altered to control the overall amount of protein that is synthesized. The RNA stability can be increased, leading to longer residency time in the cytoplasm, or decreased, leading to shortened time and less protein synthesis. RNA stability is controlled by RNA-binding proteins (RPBs) and microRNAs (miRNAs). These RPBs and miRNAs bind to the 5′ UTR or the 3′ UTR of the RNA to increase or decrease RNA stability. MicroRNAs associated with RISC complexes may repress translation or lead to mRNA breakdown.


SARS-CoV-2 contributes to altering the post-transcriptional regulatory networks across human tissues by sponging RNA binding proteins and micro-RNAs

The outbreak of a novel coronavirus SARS-CoV2 responsible for COVID-19 pandemic has caused worldwide public health emergency. Due to the constantly evolving nature of the coronaviruses, SARS-CoV-2 mediated alteration on post-transcriptional gene regulation across human tissues remains elusive. In this study, we systematically dissected the crosstalk and dysregulation of human post-transcriptional regulatory networks governed by RNA binding proteins (RBPs) and micro-RNAs (miRs), due to SARS-CoV-2 infection. We uncovered that 13 out of 29 SARS-CoV-2 encoded proteins directly interact with 51 human RBPs of which majority of them were abundantly expressed in gonadal tissues and immune cells. We further performed functional analysis of differentially expressed genes in mock treated versus SARS-CoV-2 infected lung cells that revealed an enrichment for immune response, cytokine mediated signaling, and metabolism associated genes. This study also characterized the alternative splicing events in SARS-CoV-2 infected cells compared to control demonstrating that skipped exons and mutually exclusive exons were the most abundant events that potentially contributed to differential outcomes in response to viral infection. Motif enrichment analysis on the RNA genomic sequence of SARS-CoV-2 clearly revealed an enrichment for RBPs such as SRSFs, PCBPs, ELAVs and HNRNPs illustrating the sponging of RBPs by SARS-CoV-2 genome. Similar analysis to study the interactions of miRs with SARS-CoV-2 revealed the potential for several miRs to be sponged, suggesting that these interactions may contribute to altered pos-transcriptional regulation across human tissues. Given the need to understand the interactions of SARS-CoV-2 with key pos-transcriptional regulators in the human genome, this study provides a systematic analysis to dissect the role of dysregulated post-transcriptional regulatory networks controlled by RBPs and miRs, across tissues types during SARS-CoV2 infection.

Conflict of interest statement

Conflicts of interest: The authors report no financial or other conflict of interest relevant to the subject of this article.

Figures

Protein-protein interaction network analysis suggest…

Protein-protein interaction network analysis suggest an immediate interaction of human RBPs with SARS-CoV-2…

Figure 2.. Differential expression analysis of mock…

Figure 2.. Differential expression analysis of mock treated versus SARS-CoV-2 infected primary human lung epithelial…

Alternative splicing events during SARS-CoV-2…

Alternative splicing events during SARS-CoV-2 infection. (A) Bar plot showing the genes (RBP…

Motif enrichment analysis reveals potential…

Motif enrichment analysis reveals potential human RBPs titrated by SARS-CoV-2 viral genome. (A)…

SARS-CoV-2 genome titrates the abundance…

SARS-CoV-2 genome titrates the abundance of functionally important miRs in human tissue (A)…


Engineering improved Cas13 effectors for targeted post-transcriptional regulation of gene expression

Cas13 is a family of unique RNA-targeting CRISPR-Cas effectors, making it an appealing tool for probing and perturbing RNA function. However only a few Cas13 homologs have been shown to mediate robust RNA targeting in human cells, suggesting that unknown elements may be limiting their efficacy. Furthermore, many Cas13 enzymes show high degrees of toxicity upon targeting and have not been shown to mediate specific knockdown in other cell types such as E. coli. Here, we show that catalytically inactive Cas13 enzymes can be repurposed for efficient translational repression in bacteria with no associated growth defects. To achieve this advance, we carried out a directed evolution screen to engineer functional Cas13a variants, and identified a number of stabilizing mutations, which enabled efficient post transcriptional knockdown of gene expression. In vitro characterization of the resulting engineered Lbu Cas13a mutant, termed eLbu, revealed both stabilization and altered cleavage kinetics. Finally, we show that eLbu can be used for efficient exon skipping in human cells. This work represents the first demonstration of targeted translational repression in E. coli using a CRISPR enzyme, as well as the first directed evolution of a Cas13 enzyme. Such a platform could allow for engineering other aspects of this protein family to obtain more robust RNA targeting tools.


Résumé

Au sein de la cellule, les concentrations en transcrits et en protéines sont finement régulées afin de sɺjuster en permanence aux besoins cellulaires. Récemment, plusieurs études à grande échelle, réalisées chez les procaryotes, ont mis en évidence la présence de faibles corrélations entre les concentrations des transcrits et celles des protéines, soulignant l'importance des régulations post-transcriptionnelles. Les régulations post-transcriptionnelles interviennent dans l𧫚ptation dynamique du turnover des transcrits et des protéines ainsi que dans la modulation de l𧻿icacité de traduction des ARNm en protéines. Les stabilités des transcrits et des protéines sont dépendantes de déterminants de séquence et de processus de dégradation. L𧻿icacité de traduction est quant à elle principalement modulée par la synthèse et l➬tivité des ribosomes. La réconciliation, à travers une approche de biologie intégrative, des données à grande échelle obtenues pour chaque niveau de régulation est maintenant requise afin de mieux appréhender la réponse globale de la cellule face à des variations environnementales. Dans cette revue, nous détaillerons les mécanismes impliqués chez les procaryotes dans les stabilités des transcrits et des protéines ainsi que dans la régulation de la traduction, en soulignant en particulier leur dépendance vis-à-vis des phases de croissance et des conditions environnementales. Pour citer cet article : F. Picard et al., C. R. Biologies 332 (2009).


Comparative Reproduction

Patricia Rojas-Ríos , Martine Simonelig , in Encyclopedia of Reproduction (Second Edition) , 2018

Function of Maternal mRNAs: Establishment of the Oocyte and Embryonic Polarity

Maternal mRNAs and their post-transcriptional regulation play a key role in meiotic progression and regulation of cell cycle in the oocyte and early embryo. Oocyte maturation (meiotic progression from prophase to metaphase I) that takes place in stage 12–13 oocyte is accompanied by poly(A) tail lengthening of a large set of maternal mRNAs and large-scale changes in the proteome ( Laver et al., 2015 ).

Another major function of maternal mRNAs is to establish the polarity of the Drosophila embryo, which already takes place in the oocyte. Four maternal mRNAs, oskar (osk), nanos (nos), bicoid (bcd) and gurken (grk) play key roles in embryonic axis specification ( Lasko, 2012 ). The corresponding genes were identified through genetic screens: mothers mutant for these genes produce embryos lacking embryonic structures. These maternal mRNAs are transported along microtubules from the nurse cells to the oocyte, during early stages of oogenesis, through the ring canals. Localization of these mRNAs become highly asymmetric from mid-oogenesis (stage 9) and this localization coupled to translational regulation underlies axis specification ( Fig. 2(B) ). The anterior-posterior axis is established through the localization of bcd mRNA to the anterior pole of the oocyte and the localization of osk and nos mRNAs to the posterior pole. osk mRNA is translated when it reaches the posterior pole during mid-oogenesis. Osk protein is the primary determinant of the germ plasm, a specialized cytoplasm that is required for germ cell development at the posterior pole of the oocyte ( Lehmann, 2016 ). Large RNA granules, so-called polar granules, containing mRNAs, small RNAs and proteins form in the germ plasm. Polar granules contain mRNAs encoding germ cell determinants and are essential for germline specification. Nos is one of those germ cell determinants, and is also required for abdominal development. Nos protein is expressed as a posterior to anterior gradient generated from nos mRNA localized in the germ plasm at the posterior pole. Osk is involved in the stabilization and translation of germ cell mRNAs, including nos, in the germ plasm. Osk is therefore essential for both posterior patterning and specification of the germline lineage in the embryo ( Fig. 2(B) ).

Although localized at the anterior pole of the oocyte during mid-oogenesis, bcd mRNA is translated only after egg activation -when the mature stage 14 oocyte passes through the oviduct, prior to fertilization-. Its translation depends on poly(A) tail elongation. Bcd protein is produced as a gradient from the anteriorly localized mRNA. This gradient of Bcd acting both as a transcription factor and a translational repressor, initiates a cascade of zygotic gene expression that directs anterior-posterior patterning of the embryo.

Grk is required in establishing both the anterior-posterior and dorsal-ventral axes during oogenesis. Grk is an epidermal growth factor receptor (EGFR) ligand secreted from the oocyte to locally activate EGFR in the adjacent somatic cells that surround the oocyte, the follicle cells. During early oogenesis, Grk plays a role in establishing anterior-posterior polarity by signaling to a posterior subpopulation of follicle cells to adopt a posterior fate. During mid-oogenesis, grk mRNA localizes to the antero-dorsal corner of the oocyte and produces localized protein that specifies the dorsal-ventral axis, by inducing a dorsal fate in the closest follicle cells ( Fig. 2(B) ).


Evolution Connection

How could alternative splicing evolve? Introns have a beginning- and ending-recognition sequence it is easy to imagine the failure of the splicing mechanism to identify the end of an intron and instead find the end of the next intron, thus removing two introns and the intervening exon. In fact, there are mechanisms in place to prevent such intron skipping, but mutations are likely to lead to their failure. Such “mistakes” would more than likely produce a nonfunctional protein. Indeed, the cause of many genetic diseases is abnormal splicing rather than mutations in a coding sequence. However, alternative splicing could possibly create a protein variant without the loss of the original protein, opening up possibilities for adaptation of the new variant to new functions. Gene duplication has played an important role in the evolution of new functions in a similar way by providing genes that may evolve without eliminating the original, functional protein.

Question: In the corn snake Pantherophis guttatus, there are several different color variants, including amelanistic snakes whose skin patterns display only red and yellow pigments. The cause of amelanism in these snakes was recently identified as the insertion of a transposable element into an intron in the OCA2 (oculocutaneous albinism) gene. How might the insertion of extra genetic material into an intron lead to a nonfunctional protein?


Watch the video: Post-transcriptional regulation. Biomolecules. MCAT. Khan Academy (September 2022).


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