scholarly journals Messenger RNA modifications: Form, distribution, and function

Science ◽  
2016 ◽  
Vol 352 (6292) ◽  
pp. 1408-1412 ◽  
Author(s):  
W. V. Gilbert ◽  
T. A. Bell ◽  
C. Schaening
Keyword(s):  
Messenger Rna ◽  
Rna Modifications ◽  
And Function

scholarly journals RNA modifications modulate gene expression during development

Science ◽  
2018 ◽  
Vol 361 (6409) ◽  
pp. 1346-1349 ◽  
Author(s):  
Michaela Frye ◽  
Bryan T. Harada ◽  
Mikaela Behm ◽  
Chuan He
Keyword(s):  
Gene Expression ◽  
Rna Structure ◽  
Messenger Rna ◽  
Normal Development ◽  
Biological Processes ◽  
Rna Modifications ◽  
Transfer Rnas ◽  
Mrna Metabolism ◽  
Global Protein Synthesis ◽  
And Function

RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programs. They affect diverse eukaryotic biological processes, and the correct deposition of many of these modifications is required for normal development. Messenger RNA (mRNA) modifications regulate various aspects of mRNA metabolism. For example,N6-methyladenosine (m6A) affects the translation and stability of the modified transcripts, thus providing a mechanism to coordinate the regulation of groups of transcripts during cell state maintenance and transition. Similarly, some modifications in transfer RNAs are essential for RNA structure and function. Others are deposited in response to external cues and adapt global protein synthesis and gene-specific translational accordingly and thereby facilitate proper development.

Messenger RNA modifications: clinical clarification and significance

Epigenomics ◽  
2021 ◽  
Author(s):  
Kan Pan ◽  
Gangqiang Guo ◽  
Xiangyang Xue
Keyword(s):  
Messenger Rna ◽  
Rna Modifications

scholarly journals Human granulocyte-monocyte colony-stimulating factor and interleukin 3 stimulate monocyte cytotoxicity through a tumor necrosis factor- dependent mechanism

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 672-676
Author(s):  
SA Cannistra ◽  
E Vellenga ◽  
P Groshek ◽  
A Rambaldi ◽  
JD Griffin
Keyword(s):  
Tumor Necrosis Factor ◽  
Messenger Rna ◽  
Tumor Necrosis ◽  
Tumoricidal Activity ◽  
Interleukin 3 ◽  
Gm Csf ◽  
And Function ◽  
Monocyte Cytotoxicity ◽  
Necrosis Factor ◽  
Dependent Mechanism

Human colony-stimulating factors (CSF) exert multiple effects on the proliferation, differentiation, and function of myeloid lineage cells. In this study, the effects of three recombinant human CSFs (granulocyte- monocyte CSF [GM-CSF], interleukin 3 [IL-3], and granulocyte CSF [G- CSF]) on antibody-independent monocyte tumoricidal activity were investigated by using WEHI 164 fibrosarcoma cells as monocyte-sensitive targets. None of the CSFs directly induced monocyte cytotoxicity, although both GM-CSF and IL-3 were found to significantly enhance monocyte killing in response to a second stimulatory event (endotoxin). No effect was seen with G-CSF. Antitumor necrosis factor antibody completely abolished CSF-enhanced monocyte cytotoxicity, which suggests that this effect was mediated through increased release of tumor necrosis factor (TNF). As previously shown for GM-CSF, IL-3 was found to induce cytoplasmic accumulation of TNF messenger RNA (mRNA) after 18 hours of exposure. These results suggest that GM-CSF and IL-3 may stimulate monocyte killing indirectly by enhancing expression of TNF mRNA, thereby leading to augmented TNF protein secretion in response to a second activation signal.

scholarly journals Dynamic m6A methylation facilitates mRNA triaging to stress granules

2018 ◽  
Vol 1 (4) ◽  
pp. e201800113 ◽  
Author(s):  
Maximilian Anders ◽  
Irina Chelysheva ◽  
Ingrid Goebel ◽  
Timo Trenkner ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Messenger Rna ◽  
Stress Granules ◽  
Rna Metabolism ◽  
Methylation Pattern ◽  
Domain Family ◽  
Induced Stress ◽  
And Function ◽  
Selective Mechanism

Reversible post-transcriptional modifications on messenger RNA emerge as prevalent phenomena in RNA metabolism. The most abundant among them is N6-methyladenosine (m6A) which is pivotal for RNA metabolism and function; its role in stress response remains elusive. We have discovered that in response to oxidative stress, transcripts are additionally m6A modified in their 5′ vicinity. Distinct from that of the translationally active mRNAs, this methylation pattern provides a selective mechanism for triaging mRNAs from the translatable pool to stress-induced stress granules. These stress-induced newly methylated sites are selectively recognized by the YTH domain family 3 (YTHDF3) “reader” protein, thereby revealing a new role for YTHDF3 in shaping the selectivity of stress response. Our findings describe a previously unappreciated function for RNA m6A modification in oxidative-stress response and expand the breadth of physiological roles of m6A.

scholarly journals Production and Application of Stable Isotope-Labeled Internal Standards for RNA Modification Analysis

Genes ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 26 ◽  
Author(s):  
Kayla Borland ◽  
Jan Diesend ◽  
Taku Ito-Kureha ◽  
Vigo Heissmeyer ◽  
Christian Hammann ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Isotope Labeling ◽  
Rna Stability ◽  
Internal Standard ◽  
Modified Nucleosides ◽  
Rna Modification ◽  
Mouse Tissue ◽  
Rna Modifications ◽  
Internal Standards ◽  
Translation Fidelity

Post-transcriptional RNA modifications have been found to be present in a wide variety of organisms and in different types of RNA. Nucleoside modifications are interesting due to their already known roles in translation fidelity, enzyme recognition, disease progression, and RNA stability. In addition, the abundance of modified nucleosides fluctuates based on growth phase, external stress, or possibly other factors not yet explored. With modifications ever changing, a method to determine absolute quantities for multiple nucleoside modifications is required. Here, we report metabolic isotope labeling to produce isotopically labeled internal standards in bacteria and yeast. These can be used for the quantification of 26 different modified nucleosides. We explain in detail how these internal standards are produced and show their mass spectrometric characterization. We apply our internal standards and quantify the modification content of transfer RNA (tRNA) from bacteria and various eukaryotes. We can show that the origin of the internal standard has no impact on the quantification result. Furthermore, we use our internal standard for the quantification of modified nucleosides in mouse tissue messenger RNA (mRNA), where we find different modification profiles in liver and brain tissue.

Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation

Science ◽  
2018 ◽  
Vol 361 (6403) ◽  
pp. 701-704 ◽  
Author(s):  
Jaechul Lim ◽  
Dongwan Kim ◽  
Young-suk Lee ◽  
Minju Ha ◽  
Mihye Lee ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Half Life ◽  
Messenger Rna ◽  
Mrna Translation ◽  
Posttranscriptional Gene Regulation ◽  
And Function ◽  
Mrna Half Life ◽  
In Cells

RNA tails play integral roles in the regulation of messenger RNA (mRNA) translation and decay. Guanylation of the poly(A) tail was discovered recently, yet the enzymology and function remain obscure. Here we identify TENT4A (PAPD7) and TENT4B (PAPD5) as the enzymes responsible for mRNA guanylation. Purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues, the most common of which is guanosine. A single guanosine residue is sufficient to impede the deadenylase CCR4-NOT complex, which trims the tail and exposes guanosine at the 3′ end. Consistently, depletion of TENT4A and TENT4B leads to a decrease in mRNA half-life and abundance in cells. Thus, TENT4A and TENT4B produce a mixed tail that shields mRNA from rapid deadenylation. Our study unveils the role of mixed tailing and expands the complexity of posttranscriptional gene regulation.

Loss of Fbxw7 in Sertoli cells impairs testis development and causes infertility in mice†

2019 ◽  
Vol 102 (4) ◽  
pp. 963-974
Author(s):  
Hanbin Zhang ◽  
Feilong Chen ◽  
Heling Dong ◽  
Minyu Xie ◽  
Huan Zhang ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Cell Loss ◽  
Mutant Mice ◽  
Tubular Atrophy ◽  
Testis Development ◽  
Protein Levels ◽  
Conditional Mutant ◽  
F Box Protein ◽  
And Function ◽  
Specific Deletion

Abstract F-box and WD-40 domain protein 7 (Fbxw7) is a component of the Skp1-Cdc53/Cullin-F-box-protein complex (SCF/β-TrCP), which is an E3 ubiquitin ligase that mediates protein degradation. This complex has recently been shown to negatively regulate spermatogonial stem cell self-renewal; however, its roles in Sertoli cell (SC) proliferation, differentiation, and function remain to be established. In this study, we generated conditional mutant mice with SC-specific deletion of Fbxw7 via the Cre-loxP system. Fbxw7 deficiency in SCs impaired testis development, which is characterized by age-dependent tubular atrophy, excessive germ cell loss, and spermatogenic arrest, and the mutant males were infertile at 7 months old. Fbxw7 ablation also compromised cytoskeletal organization and cell polarity of SCs, as well as integrity of the blood-testis barrier. In addition, the transcript levels of cell markers for germ cells, Leydig cells, and SCs were significantly decreased in Fbxw7 mutant mice. Importantly, protein levels of GATA-4, a transcription factor that plays a crucial role in SC maturation and testis development, were progressively decreased in control SCs after postnatal day 14, whereas levels were aberrantly elevated in Fbxw7-deleted SCs. Interestingly, the Gata-4 messenger RNA levels remained stable following Fbxw7 deletion. Fbxw7 silencing in SCs also induced progressive Leydig cell inefficiency and testosterone insufficiency. Collectively, these results demonstrate that Fbxw7 expression is required for SC maturation and function, potentially through degradation of GATA-4, to support pubertal testis development and spermatogenesis.

scholarly journals Nucleotide resolution profiling of m3C RNA modification by HAC-seq

2020 ◽  
Author(s):  
Jia Cui ◽  
Qi Liu ◽  
Erdem Sendinc ◽  
Yang Shi ◽  
Richard I Gregory
Keyword(s):  
Rna Modification ◽  
Rna Modifications ◽  
Mcf7 Cells ◽  
Single Nucleotide ◽  
Novel Method ◽  
Specific Mapping ◽  
Nucleotide Resolution ◽  
And Function ◽  
Trna Isoacceptors ◽  
Single Nucleotide Resolution

Abstract Cellular RNAs are subject to a myriad of different chemical modifications that play important roles in controlling RNA expression and function. Dysregulation of certain RNA modifications, the so-called ‘epitranscriptome’, contributes to human disease. One limitation in studying the functional, physiological, and pathological roles of the epitranscriptome is the availability of methods for the precise mapping of individual RNA modifications throughout the transcriptome. 3-Methylcytidine (m3C) modification of certain tRNAs is well established and was also recently detected in mRNA. However, methods for the specific mapping of m3C throughout the transcriptome are lacking. Here, we developed a m3C-specific technique, Hydrazine-Aniline Cleavage sequencing (HAC-seq), to profile the m3C methylome at single-nucleotide resolution. We applied HAC-seq to analyze ribosomal RNA (rRNA)-depleted total RNAs in human cells. We found that tRNAs are the predominant m3C-modified RNA species, with 17 m3C modification sites on 11 cytoplasmic and 2 mitochondrial tRNA isoacceptors in MCF7 cells. We found no evidence for m3C-modification of mRNA or other non-coding RNAs at comparable levels to tRNAs in these cells. HAC-seq provides a novel method for the unbiased, transcriptome-wide identification of m3C RNA modification at single-nucleotide resolution, and could be widely applied to reveal the m3C methylome in different cells and tissues.

scholarly journals Numerical operations in living cells by programmable RNA devices

2019 ◽  
Vol 5 (8) ◽  
pp. eaax0835 ◽  
Author(s):  
Kei Endo ◽  
Karin Hayashi ◽  
Hirohide Saito
Keyword(s):  
Messenger Rna ◽  
Design Principle ◽  
Logic Gates ◽  
Living Cells ◽  
Multiple Biomarkers ◽  
Intracellular Changes ◽  
And Function ◽  
Single Living Cells ◽  
Single Living ◽  
Numerical Operations

Integrated bioengineering systems can make executable decisions according to the cell state. To sense the state, multiple biomarkers are detected and processed via logic gates with synthetic biological devices. However, numerical operations have not been achieved. Here, we show a design principle for messenger RNA (mRNA) devices that recapitulates intracellular information by multivariate calculations in single living cells. On the basis of this principle and the collected profiles of multiple microRNA activities, we demonstrate that rationally programmed mRNA sets classify living human cells and track their change during differentiation. Our mRNA devices automatically perform multivariate calculation and function as a decision-maker in response to dynamic intracellular changes in living cells.

scholarly journals Molecular mechanisms behind mRNA localization in axons

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200177
Author(s):  
Benita Turner-Bridger ◽  
Cinzia Caterino ◽  
Jean-Michel Cioni
Keyword(s):  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Mrna Localization ◽  
Adaptive Responses ◽  
Cis Acting ◽  
Spatiotemporal Regulation ◽  
Mrna Content ◽  
Specific Mrnas ◽  
And Function

Messenger RNA (mRNA) localization allows spatiotemporal regulation of the proteome at the subcellular level. This is observed in the axons of neurons, where mRNA localization is involved in regulating neuronal development and function by orchestrating rapid adaptive responses to extracellular cues and the maintenance of axonal homeostasis through local translation. Here, we provide an overview of the key findings that have broadened our knowledge regarding how specific mRNAs are trafficked and localize to axons. In particular, we review transcriptomic studies investigating mRNA content in axons and the molecular principles underpinning how these mRNAs arrived there, including cis-acting mRNA sequences and trans-acting proteins playing a role. Further, we discuss evidence that links defective axonal mRNA localization and pathological outcomes.

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