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Gene expression factory model for coupling steps in gene expression.In this model the gene expression factory is anchored to the nuclear substructure and the DNA is reeled through the RNA polymerase as the nascent RNA is extruded through its exit channel. The machineries involved in transcription, capping, splicing and polyadenylation are shown. The shaded pink ovals over the spliced exons represent the mRNA complexes formed near the exon–exon junctions during the splicing reaction. See text for details of Parts a–f. PIC, preinitiation complex; TF, transcription factors; CTD, carboxy-terminal domain; CAP, capping factor; SF, splicing factor; pA, polyadenylation factor; P, phosphorylated CTD.
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Gene expression in eukaryotes requires several multi-component cellular machines. Each machine carries out a separate step in the gene expression pathway, which includes transcription, several pre-messenger RNA processing steps and the export of mature mRNA to the cytoplasm. Recent studies lead to the view that, in contrast to a simple linear assem...
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... working model for coupling transcription and pre-mRNA processing based on the gene expression factory model is shown in Fig. 2. In this model capping (CAP), splicing (SF) and poly- adenylation (pA) factors are recruited to the transcription preini- tiation complex (PIC) (see Fig. 2a). At this stage transcription factors (TF) are bound to the unphosphorylated CTD. Upon transcription initiation the CTD is phosphorylated, the PIC is released and capping, splicing ...
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... working model for coupling transcription and pre-mRNA processing based on the gene expression factory model is shown in Fig. 2. In this model capping (CAP), splicing (SF) and poly- adenylation (pA) factors are recruited to the transcription preini- tiation complex (PIC) (see Fig. 2a). At this stage transcription factors (TF) are bound to the unphosphorylated CTD. Upon transcription initiation the CTD is phosphorylated, the PIC is released and capping, splicing and polyadenylation components associate with the CTD (Fig. 2b). Shortly after pre-mRNA synthesis begins, the 59 end is capped, and the capping machinery ...
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... and poly- adenylation (pA) factors are recruited to the transcription preini- tiation complex (PIC) (see Fig. 2a). At this stage transcription factors (TF) are bound to the unphosphorylated CTD. Upon transcription initiation the CTD is phosphorylated, the PIC is released and capping, splicing and polyadenylation components associate with the CTD (Fig. 2b). Shortly after pre-mRNA synthesis begins, the 59 end is capped, and the capping machinery then dissociates from the CTD (Fig. 2b). As the DNA is reeled into the gene expression factory, and the nascent pre-mRNA is extruded through the exit channel of the RNA polymerase, splicing factors are systematically transferred from the CTD to ...
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... transcription factors (TF) are bound to the unphosphorylated CTD. Upon transcription initiation the CTD is phosphorylated, the PIC is released and capping, splicing and polyadenylation components associate with the CTD (Fig. 2b). Shortly after pre-mRNA synthesis begins, the 59 end is capped, and the capping machinery then dissociates from the CTD (Fig. 2b). As the DNA is reeled into the gene expression factory, and the nascent pre-mRNA is extruded through the exit channel of the RNA polymerase, splicing factors are systematically transferred from the CTD to the exons (Fig. 2c), where they recruit the rest of the splicing machinery. Splicing factors are also transferred via the elongation ...
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... 2b). Shortly after pre-mRNA synthesis begins, the 59 end is capped, and the capping machinery then dissociates from the CTD (Fig. 2b). As the DNA is reeled into the gene expression factory, and the nascent pre-mRNA is extruded through the exit channel of the RNA polymerase, splicing factors are systematically transferred from the CTD to the exons (Fig. 2c), where they recruit the rest of the splicing machinery. Splicing factors are also transferred via the elongation complex (not shown). The interaction between splicing factors bound to the CTD with those bound to the exon functions to tether the exon to the CTD until the next exon emerges from the exit pore of the polymerase (Fig. 2d). ...
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... to the exons (Fig. 2c), where they recruit the rest of the splicing machinery. Splicing factors are also transferred via the elongation complex (not shown). The interaction between splicing factors bound to the CTD with those bound to the exon functions to tether the exon to the CTD until the next exon emerges from the exit pore of the polymerase (Fig. 2d). This tethering plays a role in recognizing exons, and in ensuring the correct 59 and 39 association of sequentially synthesized exons. The splicing factors transferred from the CTD to the nascent pre-mRNA review article are rapidly replaced by new splicing factors which are optimally positioned for the appearance of the next exon. ...
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... leads to the formation of a speci®c complex of proteins on the spliced exons (messenger RNA±ribonucleoprotein (mRNP) complex, described below). When the polymerase approaches the end of the transcript, the polyadenylation factors function (Fig. 2e). Finally the CTD is dephosphorylated, the processing factors are released and the mature mRNP is released from the site of transcription (Fig. ...
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... of proteins on the spliced exons (messenger RNA±ribonucleoprotein (mRNP) complex, described below). When the polymerase approaches the end of the transcript, the polyadenylation factors function (Fig. 2e). Finally the CTD is dephosphorylated, the processing factors are released and the mature mRNP is released from the site of transcription (Fig. ...
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... Some RNA-binding proteins can remain associated with mRNAs across multiple stages: RNA processing, transport, translation, or translational control [2,[95][96][97][98][99]. Ataxin-2 may be one such protein. ...
Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.
... There is also good evidence that changes in the recruitment of splicing factors in response to changes in the phosphorylation of the CTD of RNAPII during transcriptional elongation can regulate alternative splicing [31]. Chromatin conformation, nucleosome placement, and histone modifications can also regulate alternative splicing through changing the RNAPII elongation rate, but also by differential recruitment of splicing factor [32]. Next, different nuclear RNA processing steps are tightly linked through RNAPII and co-transcriptional RNA processing and by associated RBPs, which can be shared by several different steps in mRNA biogenesis [33,34]. For example, splicing proteins can regulate nascent RNA cleavage and polyadenylation both positively and negatively, and cleavage and polyadenylation can control splicing of upstream exons [35]. ...
... In summary, there is a very strong connection between DDR and alternative splicing. Next, different nuclear RNA processing steps are tightly linked through RNAPII and co-transcriptional RNA processing and by associated RBPs, which can be shared by several different steps in mRNA biogenesis [33,34]. For example, splicing proteins can regulate nascent RNA cleavage and polyadenylation both positively and negatively, and cleavage and polyadenylation can control splicing of upstream exons [35]. ...
Papillomavirus gene regulation is largely post-transcriptional due to overlapping open reading frames and the use of alternative polyadenylation and alternative splicing to produce the full suite of viral mRNAs. These processes are controlled by a wide range of cellular RNA binding proteins (RPBs), including constitutive splicing factors and cleavage and polyadenylation machinery, but also factors that regulate these processes, for example, SR and hnRNP proteins. Like cellular RNAs, papillomavirus RNAs have been shown to bind many such proteins. The life cycle of papillomaviruses is intimately linked to differentiation of the epithelial tissues the virus infects. For example, viral late mRNAs and proteins are expressed only in the most differentiated epithelial layers to avoid recognition by the host immune response. Papillomavirus genome replication is linked to the DNA damage response and viral chromatin conformation, processes which also link to RNA processing. Challenges with respect to elucidating how RBPs regulate the viral life cycle include consideration of the orchestrated spatial aspect of viral gene expression in an infected epithelium and the epigenetic nature of the viral episomal genome. This review discusses RBPs that control viral gene expression, and how the connectivity of various nuclear processes might contribute to viral mRNA production.
... Export of mature mRNAs from the cell nucleus is intimately coupled to transcription and pre-mRNA processing, and the TREX complex plays a central role in the coordination of these processes (Maniatis & Reed, 2002;Moore & Proudfoot, 2009;Wickramasinghe & Laskey, 2015;Heath et al., 2016). The yeast and mammalian MOS11 orthologs, Tho1 and CIP29/SARNP, were identified as TREX components that exhibit RNA-binding activity. ...
Transcription and export (TREX) is a multi‐subunit complex that links synthesis, processing and export of mRNAs. It interacts with the RNA helicase UAP56 and export factors such as MOS11 and ALYs to facilitate nucleocytosolic transport of mRNAs. Plant MOS11 is a conserved, but sparsely researched RNA‐binding export factor, related to yeast Tho1 and mammalian CIP29/SARNP.
Using biochemical approaches, the domains of Arabidopsis thaliana MOS11 required for interaction with UAP56 and RNA‐binding were identified. Further analyses revealed marked genetic interactions between MOS11 and ALY genes. Cell fractionation in combination with transcript profiling demonstrated that MOS11 is required for export of a subset of mRNAs that are shorter and more GC‐rich than MOS11‐independent transcripts.
The central α‐helical domain of MOS11 proved essential for physical interaction with UAP56 and for RNA‐binding. MOS11 is involved in the nucleocytosolic transport of mRNAs that are upregulated under stress conditions and accordingly mos11 mutant plants turned out to be sensitive to elevated NaCl concentrations and heat stress.
Collectively, our analyses identify functional interaction domains of MOS11. In addition, the results establish that mRNA export is critically involved in the plant response to stress conditions and that MOS11 plays a prominent role at this.
... 32,43,44 Yang et al. 45 suggested the role of intronic variants in regulating gene expression. The introns also play a pivotal role in mRNA export, transcription coupling, splicing etc. 46 Absence of polymorphism in the studied coding region of the camelid's TLR4 gene, depicted the unique genomic architecture suggesting either possible selective pressure being exerted on the gene, and/or the role of other innate immune system components in camelids' evolution and adaptation. Researchers have also reported a low level of polymorphism in Major Histocompatibility Complex class II genes in old-world camels as compared to other mammalian species. ...
Our study aimed to explore the genetic variation in the Toll-like receptor 4 (TLR4) gene and establish its association with somatic cell score (SCS) and milk production traits in four Indian camel breeds namely Bikaneri, Kachchhi, Jaisalmeri and Mewari. TLR4 gene fragment of 573 bp spanning 5' UTR, exon-1 and partial intron-1 region was amplified and genotyped using the PCR-sequence based typing method. Only one SNP located at position C472T was identified. Genotyping revealed two alleles (C and T) and three genotypes: CC, CT and TT. The genotype frequencies for CC, CT and TT were 0.116, 0.326 and 0.558 and allele frequencies for C and T alleles were 0.279 and 0.721, respectively. Association study inferred that the effect of genotype on SCS, lactation yield (LY) and peak yield (PY) was non-significant however heterozygote (CT) genotypes recorded lower SCS and higher LY and PY. It can be concluded that the TLR4 gene possesses limited genetic variation, depicting polymorphism at a single locus in Indian camel breeds with a predominance of the TT genotype. The association study indicated that heterozygote animals possess better udder health and production performance, the statistical significance of which needs to be established using a large data set.
... Eukaryotic gene expression of protein-coding genes involves transcription, RNA processing, RNA export, translation, and degradation of transcripts (Maniatis and Reed 2002;Keene 2007;Bentley 2014;Braun and Young 2014). All of these processes are independently regulated, but interlinked to ensure tailored expression control. ...
A-to-I RNA editing is a widespread epitranscriptomic phenomenon leading to the conversion of adenosines to inosines, which are primarily interpreted as guanosines by cellular machines. Consequently, A-to-I editing can alter splicing or lead to recoding of transcripts. As misregulation of editing can cause a variety of human diseases, A-to-I editing requires tight regulation of the extent of deamination, particularly in protein-coding regions. The bulk of A-to-I editing occurs cotranscriptionally. Thus, we studied A-to-I editing regulation in the context of transcription and pre-mRNA processing. We show that stimulation of transcription impacts editing levels. Activation of the transcription factor MYC leads to an up-regulation of A-to-I editing, particularly in transcripts that are suppressed upon MYC activation. Moreover, low pre-mRNA synthesis rates and low pre-mRNA expression levels support high levels of editing. We also show that editing levels greatly differ between nascent pre-mRNA and mRNA in a cellular system, as well as in mouse tissues. Editing levels can increase or decrease from pre-mRNA to mRNA and can vary across editing targets and across tissues, showing that pre-mRNA processing is an important layer of editing regulation. Several lines of evidence suggest that the differences emerge during pre-mRNA splicing. Moreover, actinomycin D treatment of primary neuronal cells and editing level analysis suggests that regulation of editing levels also depends on transcription.
... Eukaryotic gene expression involves a series of highly coordinated steps, starting from transcription and splicing of mRNA precursors ( pre-mRNAs ) , followed by mRNA export, translation and decay ( 16 ) . These steps require multicomponent cellular machines that are tethered to each other ( 16 ) . ...
... Eukaryotic gene expression involves a series of highly coordinated steps, starting from transcription and splicing of mRNA precursors ( pre-mRNAs ) , followed by mRNA export, translation and decay ( 16 ) . These steps require multicomponent cellular machines that are tethered to each other ( 16 ) . In humans, the most complex step is believed to be pre-mRNA splicing, which removes intervening sequences or introns and joins coding sequences or exons together with single-nucleotide precision. ...
Exonic sequences contain both protein-coding and RNA splicing information but the interplay of the protein and splicing code is complex and poorly understood. Here, we have studied traditional and auxiliary splicing codes of human exons that encode residues coordinating two essential divalent metals at the opposite ends of the Irving–Williams series, a universal order of relative stabilities of metal–organic complexes. We show that exons encoding Zn2+-coordinating amino acids are supported much less by the auxiliary splicing motifs than exons coordinating Ca2+. The handicap of the former is compensated by stronger splice sites and uridine-richer polypyrimidine tracts, except for position –3 relative to 3′ splice junctions. However, both Ca2+ and Zn2+ exons exhibit close-to-constitutive splicing in multiple tissues, consistent with their critical importance for metalloprotein function and a relatively small fraction of expendable, alternatively spliced exons. These results indicate that constraints imposed by metal coordination spheres on RNA splicing have been efficiently overcome by the plasticity of exon–intron architecture to ensure adequate metalloprotein expression.
... A key question remains: Where in the nucleus does eIF4E interact with this splicing and other processing machinery? Generally speaking, capping, splicing, and CPA occur close to sites of transcription [1][2][3] ; however, these events can also occur posttranscriptionally ( Figure 1A,B). [4,5] If eIF4E associated with sites of transcription it would provide a clear model by which eIF4E modulated multiple processes synchronously. ...
Recent findings position the eukaryotic translation initiation factor eIF4E as a novel modulator of mRNA splicing, a process that impacts the form and function of resultant proteins. eIF4E physically interacts with the spliceosome and with some intron‐containing transcripts implying a direct role in some splicing events. Moreover, eIF4E drives the production of key components of the splicing machinery underpinning larger scale impacts on splicing. These drive eIF4E‐dependent reprogramming of the splicing signature. This work completes a series of studies demonstrating eIF4E acts in all the major mRNA maturation steps whereby eIF4E drives production of the RNA processing machinery and escorts some transcripts through various maturation steps. In this way, eIF4E couples the mRNA processing‐export‐translation axis linking nuclear mRNA processing to cytoplasmic translation. eIF4E elevation is linked to worse outcomes in acute myeloid leukemia patients where these activities are dysregulated. Understanding these effects provides new insight into post‐transcriptional control and eIF4E‐driven cancers.
... Networks equip us with a statistical approach to model real-world complex systems based on underlying interaction networks [1]. For instance, in cellular activities, biomolecules interact to perform diverse functions which can be studied through protein-protein interactions [2], gene-transcription factor interactions [3], and metabolic interactions [4] networks. Using the network framework, biologists have analyzed complex sub-cellular interactions to access various structural and evolutionary functionality of cells [5]. ...
... It is to note that despite having very low variable sites in the low-altitude, tRNA genes, Trp, Tyr, Gly, and Ser are contributing to the highest node degree. When the difference (∆d(v)) of pair-wise (d(v) n,2 ) and triangle degrees (d(v) n, 3 ) was plotted, we found that certain variable sites were having large differences compared to most of the other variable sites. This suggests that a few variable sites show a higher tendency to form hyperedges (figure 4 upper panel). ...
... Since more than one edge can belong to the same gene pair, we get the gene-pair weight by adding the edge degree for all the edges of a given gene pair. For instance, edges (1,2) and (3,4) are part of two triangles each. Therefore, the edge degree of both these edges will be equal to 2. Next, mapping these edges to genes, both edges belong to the same gene-pair G1-G2. ...
Pair-wise co-mutation networks of the mitochondrial genome have already provided ample evidences about the roles of genetic interactions in the manifestation of phenotype under altered environmental conditions. Here, we present a method to construct and analyze higher-order interactions, namely, 3-uniform hypergraphs of the mitochondrial genome for different altitude populations to decipher the role of co-mutating variable sites beyond pair-wise interactions. While the weights distribution of such gene hyperedges manifested power-law for all the altitudes, we identified altitude-specific genes based on gene hyperedge weight. This framework of hypergraphs serves a promising avenue for future investigation of nuclear genomes in context of phenotypic association and genetic disorders.
... Intron functions include many regulatory elements involved in gene transcription and RNA processing as well as numerous noncoding RNAs, including microRNAs and snoRNAs. [25][26][27] Both introns and exons are essential eukaryotic genome components. 28,29 Both introns and exons are genomic sequences that play an important role in maintaining the biological activity and optimal spatial structure of chromosomes prior to transcription; therefore, they need to share coevolutionary elements to perform their respective biological functions. ...
Background:
Cretinism is a subtype of congenital hypothyroidism, an endocrine disorder resulting from inadequate thyroid hormone production or receptor deficiency. Genetic abnormalities play a major role in the development of thyroid dysfunction.
Methods:
We recruited 183 participants with cretinism and 119 healthy participants from the Xinjiang Uyghur Autonomous Region and randomly selected 29 tag single nucleotide polymorphisms (tSNPs) in TSHB, PAX8, TPO, NKX2-5, and TSHR in all participants. We compared genotype and allele frequencies between cases and controls utilizing the chi-squared test, logistic regression analysis, and haplotype analysis.
Results:
Using the chi-squared test, a single SNP was found to be associated with cretinism (recessive model: rs3754363, OR = 0.46, 95% CI = 0.27-0.80, P = 0.00519; genotype model: P = 0.01677). We stratified neurological, myxedematous, and mixed type and determined that another SNP was associated with a higher risk when comparing myxedematous type to the neurological type (rs2277923).
Conclusion:
rs3754363 has a statistically significant protective effect on people with cretinism, while rs2277923 may play a greater role in promoting the development of neurocretinism.
... Gene expression undergoes post-transcriptional regulation by multiple steps via mRNA splicing, mRNA export from the nucleus to the cytosol, mRNA stability, and mRNA translation to produce proteins [1,2]. N6-methyladenosine (m 6 A) methylation, initially discovered in the 1970s, is the most abundant modification of mRNA in eukaryotes [3]. ...
RNA modifications play a vital role in multiple pathways of mRNA metabolism, and translational regulation is essential for immune cells to promptly respond to stimuli and adapt to the microenvironment. N6-methyladenosine (m⁶A) methylation, which is the most abundant mRNA modification in eukaryotes, primarily functions in the regulation of RNA splicing and degradation. However, the role of m⁶Amethylation in translational control and its underlying mechanism remain controversial. The role of m⁶A methylation in translation regulation in immune cells has received relatively limited attention. In this review, we aim to provide a comprehensive summary of current studies on the translational regulation of m⁶A modifications and recent advances in understanding the translational control regulated by RNA modifications during the immune response. Furthermore, we envision the possible pathways through which m⁶A modifications may be involved in the regulation of immune cell function via translational control.
