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2021 ◽  
Vol 22 (18) ◽  
pp. 9980
Author(s):  
Ganesh R. Koshre ◽  
Feba Shaji ◽  
Neeraja K. Mohanan ◽  
Nimmy Mohan ◽  
Jamshaid Ali ◽  
...  

Star-PAP is a non-canonical poly(A) polymerase that selects mRNA targets for polyadenylation. Yet, genome-wide direct Star-PAP targets or the mechanism of specific mRNA recognition is still vague. Here, we employ HITS-CLIP to map the cellular Star-PAP binding landscape and the mechanism of global Star-PAP mRNA association. We show a transcriptome-wide association of Star-PAP that is diminished on Star-PAP depletion. Consistent with its role in the 3′-UTR processing, we observed a high association of Star-PAP at the 3′-UTR region. Strikingly, there is an enrichment of Star-PAP at the coding region exons (CDS) in 42% of target mRNAs. We demonstrate that Star-PAP binding de-stabilises these mRNAs indicating a new role of Star-PAP in mRNA metabolism. Comparison with earlier microarray data reveals that while UTR-associated transcripts are down-regulated, CDS-associated mRNAs are largely up-regulated on Star-PAP depletion. Strikingly, the knockdown of a Star-PAP coregulator RBM10 resulted in a global loss of Star-PAP association on target mRNAs. Consistently, RBM10 depletion compromises 3′-end processing of a set of Star-PAP target mRNAs, while regulating stability/turnover of a different set of mRNAs. Our results establish a global profile of Star-PAP mRNA association and a novel role of Star-PAP in the mRNA metabolism that requires RBM10-mRNA association in the cell.


2021 ◽  
Author(s):  
Yuta Otani ◽  
Toshiki Kameyama ◽  
Akila Mayeda

Using the TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that the mRNA re-splicing is controlled by specific repressors and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knock-down of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.


Development ◽  
2021 ◽  
pp. dev.196295
Author(s):  
Xiaoli Wang ◽  
Yujiao Wen ◽  
Jin Zhang ◽  
Grace Swanson ◽  
Shuangshuang Guo ◽  
...  

Mitochondria play a critical role in spermatogenesis and are regulated by several mitochondrial fusion proteins. However, their functional importance associated with their structure formation and mRNA fate regulation during spermatogenesis remains unclear. Here, we show that Mitofusin 2 (MFN2), a mitochondrial fusion protein, interacts with Nuage-associated proteins (including MIWI, DDX4, TDRKH, and GASZ). Conditional mutation of Mfn2 in postnatal germ cells results in male sterility due to germ cell developmental defects. Moreover, MFN2 interacts with MFN1, another mitochondrial fusion protein with a high-sequence similarity to MFN2, in testes to facilitate spermatogenesis. Simultaneous mutation of Mfn1 and Mfn2 in testes causes very severe infertile phenotypes. Importantly, we show that MFN2 is enriched in polysome fractions of testes and interacts with MSY2, a germ cell-specific DNA/RNA-binding protein to control gamete-specific mRNA (such as Spata19) translational activity during spermatogenesis. Collectively, our findings demonstrate that MFN2 interacts with Nuage-associated proteins and MSY2 to regulate male germ cell development by controlling several gamete-specific mRNA fates.


2021 ◽  
Vol 220 (3) ◽  
Author(s):  
Galal Yahya ◽  
Alexis P. Pérez ◽  
Mònica B. Mendoza ◽  
Eva Parisi ◽  
David F. Moreno ◽  
...  

Stress granules (SGs) are conserved biomolecular condensates that originate in response to many stress conditions. These membraneless organelles contain nontranslating mRNAs and a diverse subproteome, but our knowledge of their regulation and functional relevance is still incipient. Here, we describe a mutual-inhibition interplay between SGs and Cdc28, the budding yeast Cdk. Among Cdc28 interactors acting as negative modulators of Start, we have identified Whi8, an RNA-binding protein that localizes to SGs and recruits the mRNA of CLN3, the most upstream G1 cyclin, for efficient translation inhibition and Cdk inactivation under stress. However, Whi8 also contributes to recruiting Cdc28 to SGs, where it acts to promote their dissolution. As predicted by a mutual-inhibition framework, the SG constitutes a bistable system that is modulated by Cdk. Since mammalian cells display a homologous mechanism, we propose that the opposing functions of specific mRNA-binding proteins and Cdk’s subjugate SG dynamics to a conserved hysteretic switch.


PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244505
Author(s):  
Yanwu Guo ◽  
Cristina Tocchini ◽  
Rafal Ciosk

Nonsense-mediated mRNA decay (NMD) controls eukaryotic mRNA quality, inducing the degradation of faulty transcripts. Key players in the NMD pathway were originally identified, through genetics, in Caenorhabditis elegans as smg (suppressor with morphological effect on genitalia) genes. Using forward genetics and fluorescence-based NMD reporters, we reexamined the genetic landscape underlying NMD. Employing a novel strategy for mapping sterile mutations, Het-Map, we identified clk-2, a conserved gene previously implicated in DNA damage signaling, as a player in the nematode NMD. We find that CLK-2 is expressed predominantly in the germline, highlighting the importance of auxiliary factors in tissue-specific mRNA decay. Importantly, the human counterpart of CLK-2/TEL2, TELO2, has been also implicated in the NMD, suggesting a conserved role of CLK-2/TEL2 proteins in mRNA surveillance. Recently, variants of TELO2 have been linked to an intellectual disability disorder, the You-Hoover-Fong syndrome, which could be related to its function in the NMD.


BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Sonia Rey ◽  
Xingkun Jin ◽  
Børge Damsgård ◽  
Marie-Laure Bégout ◽  
Simon Mackenzie

Abstract Background Consistent individual differences in behaviour, known as animal personalities, have been demonstrated within and across species. In fish, studies applying an animal personality approach have been used to resolve variation in physiological and molecular data suggesting a linkage, genotype-phenotype, between behaviour and transcriptome regulation. In this study, using three fish species (zebrafish; Danio rerio, Atlantic salmon; Salmo salar and European sea bass; Dicentrarchus labrax), we firstly address whether personality-specific mRNA transcript abundances are transferrable across distantly-related fish species and secondly whether a proactive transcriptome signature is conserved across all three species. Results Previous zebrafish transcriptome data was used as a foundation to produce a curated list of mRNA transcripts related to animal personality across all three species. mRNA transcript copy numbers for selected gene targets show that differential mRNA transcript abundance in the brain appears to be partially conserved across species relative to personality type. Secondly, we performed RNA-Seq using whole brains from S. salar and D. labrax scoring positively for both behavioural and molecular assays for proactive behaviour. We further enriched this dataset by incorporating a zebrafish brain transcriptome dataset specific to the proactive phenotype. Our results indicate that cross-species molecular signatures related to proactive behaviour are functionally conserved where shared functional pathways suggest that evolutionary convergence may be more important than individual mRNAs. Conclusions Our data supports the proposition that highly polygenic clusters of genes, with small additive effects, likely support the underpinning molecular variation related to the animal personalities in the fish used in this study. The polygenic nature of the proactive brain transcriptome across all three species questions the existence of specific molecular signatures for proactive behaviour, at least at the granularity of specific regulatory gene modules, level of genes, gene networks and molecular functions.


2021 ◽  
Vol 33 (2) ◽  
pp. 130
Author(s):  
L. K. Zhu ◽  
H. Ming ◽  
S. C. Liu ◽  
R. Iyyappan ◽  
E. D. Llano ◽  
...  

Transcriptomic analyses of early mammalian embryos from multiple species have been comprehensively conducted in the last decade. However, mRNAs detected from overall transcriptomic profile of an embryo or a single cell do not necessarily represent their functional status, as there is a gap between the overall transcriptome and mRNAs that are actively translated. Ribosome profiling has been developed to infer the translational status of a specific mRNA species and thus analyse the genome-wide translatome. However, the broad application of ribosome profiling has been slowed by its complexity and the difficulty of adapting it to low-input samples such as embryos. In this study, we developed an ultra-low-input ribosome profiling protocol optimized for mammalian embryos and systematically analysed both polysome- and non-polysome-bound mRNA profiles of invitro-produced bovine blastocysts. Ten equal fractions were collected by means of sucrose density gradient and ultracentrifugation of lysates from 100 pooled blastocysts (n=2 pools), and subjected to RNA isolation and RNA sequencing. Our bioinformatics analyses of the mRNA profiles from each fraction along with the whole-transcriptome data revealed that compared with the overall transcriptome, there is a strong selection of mRNAs in the ribosome- and polysome-associated fractions, including transcriptional factors (e.g. POU5F1, ESRRB, AQP3, and APOA1) and genes involved in ribosome biogenesis, oxidative phosphorylation, and metabolic pathways, many of which are essential for the function of embryo implantation. We also identified novel epigenetic regulators selectively translated, including regulatory enzymes on histone modifications and RNA modifications (e.g. JMJD7, ALKBH4, ALKBH7, and METTL26). In addition, we confirmed the translation of the highly expressed, yet developmentally essential pathways in the blastocysts (e.g. Wnt and Notch signalling pathways). The selectively translated mRNAs were further validated by immunofluorescent staining at the protein level and cross-validated in both bovine and mouse blastocysts. Some of these genes show only modest expression in the overall transcriptome data. Their selective translation at the blastocyst stage is only being revealed by the ribosome fractions analyses, and their functions warrant future detailed investigations. In conclusion, this study reveals bona fide active translating mRNAs in the mammalian blastocyst. The low-input ribosome profiling protocol and the data presented here set an example and open future avenues for detailed ribosome fraction–based translatome analyses to reveal novel cellular/embryonic functional regulators beyond transcriptomic data.


2020 ◽  
Author(s):  
Ubaid Qayoom ◽  
Zahoor Mushtaq

Ribonucleic acid interference (RNAi), a valuable tool for manipulating gene functionality in the laboratory, has also emerged as a powerful tool to suppress infection or replication of many pathogens that cause severe economic losses in fish farming. By taking advantage of the cell’s endogenous RNAi apparatus, small interfering RNA of ~21-22 bp can be introduced into cells to induce target specific mRNA degradation. With the growing appreciation for the potential of RNAi technology, the diversity in vivo relevance to aquaculture is seemingly vast. Studies in the future should address the hurdles like delivery strategy stability and degradation of RNAi therapeutic molecule by nucleases in aquatic animals. In this article, we review the literature in the field of RNAi technology in aquaculture, summarize the status and prospects, which may open doors to its applicability potential as a therapeutic strategy to modulate host-pathogen interactions and inspire further trials.


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