Gene regulation depends on dynamic and reversibly modifiable biological and chemical information in the epigenome/epitranscriptome. Accumulating evidence suggests that messenger RNAs (mRNAs) are generated in flashing bursts in the cells in a precisely regulated manner. However, the different aspects of the underlying mechanisms are not fully understood. Cellular RNAs are post-transcriptionally modified at the base level, which alters the metabolism of mRNA. The current understanding of epitranscriptome in the animal system is far ahead of that in plants. The accumulating evidence indicates that the epitranscriptomic changes play vital roles in developmental processes and stress responses in plants. Despite being widely detected and having well-known functions in ribosomal-RNAs and transfer-RNAs, different aspects of base modifications in mRNAs are far from adequate to assign the molecular basis and functions of the epitranscriptomic changes. Recent advances in the chemogenetic RNA-labelling and high-throughput next-generation sequencing techniques have enabled functional analysis of the epitranscriptomic modifications to reveal their roles in mRNA biology. Mapping of the common mRNA modifications, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), and pseudouridine, has enabled the identification of other types of modifications, such as N1-methyladenosine. Methylation of bases in a transcript dynamically regulates the processing, cellular export, translation, and stability of the mRNA; thereby influence the important biological and physiological processes. Here, we summarise the findings in the field of mRNA base modifications with special emphasis on m6A, m5C, and their roles in plant growth, development, and stress tolerance, which provides a new perspective for the regulation of gene expression through post-transcriptional modification. This review also presents the complementary roles of epigenome and epitranscriptome in the regulation of gene expression, addresses some of the scientific and technical issues in epitranscriptomic study, put forward the viewpoints to resolve the issues, and discusses the future perspectives of the research in this area.

/pdf/deciphering-epitranscriptome-modification-of-mrna-bases-4znp5qinyh.pdf

Deciphering Epitranscriptome: Modification of mRNA Bases Provides a New Perspective for Post-transcriptional Regulation of Gene Expression.

Post-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3-methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase that mediates the formation of the majority of 1MH present in mouse and human proteomes. METTL9-catalyzed methylation requires a His-x-His (HxH) motif, where “x” is preferably a small amino acid, allowing METTL9 to methylate a number of HxH-containing proteins, including the immunomodulatory protein S100A9 and the NDUFB3 subunit of mitochondrial respiratory Complex I. Notably, METTL9-mediated methylation enhances respiration via Complex I, and the presence of 1MH in an HxH-containing peptide reduced its zinc binding affinity. Our results establish METTL9-mediated 1MH as a pervasive protein modification, thus setting the stage for further functional studies on protein histidine methylation.

/pdf/the-methyltransferase-mettl9-mediates-pervasive-1-12io0yeass.pdf

The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes.

Significance Arsenic is a centuries-old, naturally occurring toxicant, and its cellular effect is still poorly understood. The significance of this work is three-fold. First, among a battery of oxidizing and alkylating agents, arsenite exposure caused a unique reprogramming of wobble queuosine in the transfer RNA (tRNA) epitranscriptome, which depended upon the micronutrient precursor queuine and was linked to codon-biased shifts in the translation of metabolic proteins known to be linked to arsenite toxicity. Second, we showed that the tRNA epitranscriptome is dynamically and differentially regulated by exposure to a variety of toxicants. Finally, the results have implications for the role of queuine as a micronutrient that determines the human cell response to toxic stresses.

/pdf/arsenite-toxicity-is-regulated-by-queuine-availability-and-2um31iy1.pdf

Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome

Recently, a -105G>A promoter polymorphism coding for selenoprotein S (SELS) has been shown to increase proinflammatory cytokine expression. We, therefore, analyzed SELS expression and potential phenotypic consequences of the -105G>A polymorphism in patients with inflammatory bowel disease (IBD). SELS mRNA was measured by quantitative polymerase chain reaction (PCR) in intestinal epithelial cells (IEC) after stimulation with proinflammatory cytokines and in human colonic biopsies of IBD patients as well as in murine models of ileitis and murine cytomegalovirus (MCMV) colitis. Genomic DNA from 563 individuals (Crohn's disease: n = 205; ulcerative colitis: n = 154; controls: n = 204) was analyzed for the presence of the SELS-105G>A polymorphism and the three nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/caspase recruitment domain-containing protein 15 (CARD15) variants p.Arg702Trp, p.Gly908Arg and p.Leu1007fsX1008. SELS mRNA expression was increased in IEC after stimulation with proinflammatory cytokines, while its expression was not significantly altered in murine ileitis and MCMV colitis and in inflamed ileal and colonic lesions in IBD patients compared with normal controls. The SELS-105G>A polymorphism was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype or serum tumor necrosis factor alpha (TNF-alpha) levels in these patients. Medium serum TNF-alpha was 1.27 pg/ml in IBD patients, while none of the controls had TNF-alpha concentrations above the detection threshold (P < 0.0001). SELS mRNA expression is upregulated by proinflammatory cytokines in IECs but the SELS-105G>A polymorphism is not associated with IBD susceptibility and does not contribute to a certain disease phenotype or increased TNF-alpha levels in IBD patients.

The role of the selenoprotein S (SELS) gene -105G>A promoter polymorphism in inflammatory bowel disease and regulation of SELS gene expression in intestinal inflammation

Transfer RNA[Ser]Sec carries multiple post-transcriptional modifications. The A37G mutation in tRNA[Ser]Sec abrogates isopentenylation of base 37 and has a profound effect on selenoprotein expression in mice. Patients with a homozygous pathogenic p.R323Q variant in tRNA-isopentenyl-transferase (TRIT1) show a severe neurological disorder, and hence we wondered whether selenoprotein expression was impaired. Patient fibroblasts with the homozygous p.R323Q variant did not show a general decrease in selenoprotein expression. However, recombinant human TRIT1R323Q had significantly diminished activities towards several tRNA substrates in vitro. We thus engineered mice conditionally deficient in Trit1 in hepatocytes and neurons. Mass-spectrometry revealed that hypermodification of U34 to mcm5Um occurs independently of isopentenylation of A37 in tRNA[Ser]Sec. Western blotting and 75Se metabolic labeling showed only moderate effects on selenoprotein levels and 75Se incorporation. A detailed analysis of Trit1-deficient liver using ribosomal profiling demonstrated that UGA/Sec re-coding was moderately affected in Selenop, Txnrd1, and Sephs2, but not in Gpx1. 2′O-methylation of U34 in tRNA[Ser]Sec depends on FTSJ1, but does not affect UGA/Sec re-coding in selenoprotein translation. Taken together, our results show that a lack of isopentenylation of tRNA[Ser]Sec affects UGA/Sec read-through but differs from a A37G mutation.

The Effect of tRNA[Ser]Sec Isopentenylation on Selenoprotein Expression

The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a transfer RNA (tRNA) methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized trans...

https://www.tandfonline.com/doi/pdf/10.1080/15592294.2020.1750213

The epitranscriptomic writer ALKBH8 drives tolerance and protects mouse lungs from the environmental pollutant naphthalene.

Background The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a tRNA methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation, via stop codon recoding, of proteins that contain selenocysteine. Corresponding selenoproteins play critical roles in protecting against reactive oxygen species and environmental stress. Using a novel animal model deficient in Alkbh8, we have investigated the importance of epitranscriptomic systems in the response to naphthalene (NA), an abundant polycyclic aromatic hydrocarbon, glutathione depleter and lung toxicant found in tobacco smoke, gasoline and mothballs. Objectives Our goal was to define the molecular reprogramming of Alkbh8 deficient (Alkbh8def) mice and evaluate the roles that the epitranscriptomic writer ALKBH8 and selenoproteins play in mitigating NA-induced toxicity and lung dysfunction. Methods We performed basal lung analysis and NA exposure studies using WT, Alkbh8def and Cyp2abfgs-null mice, the latter of which lack the cytochrome P450 enzymes required for NA bioactivation. We characterized gene expression, molecular markers of damage, viability and tolerance to NA. Results Under basal conditions, lungs from Alkbh8def mice have increased oxidation-reduction potential (ORP) and 8-isoprostane levels, and have reprogrammed at the molecular level to display increased stress response transcripts. In addition, the ALKBH8 writer deficient lungs have a decreased GSH/GSSG ratio. Alkbh8def mice are more sensitive to NA than WT, showing higher susceptibility to lung damage both at the cellular and molecular levels. WT mice develop a tolerance to NA after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in Alkbh8def mice, with writer deficient not surviving NA exposure. Discussion We conclude that the epitranscriptomic writer ALKBH8 plays a protective role against NA-induced lung dysfunction and promotes NA tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress in vivo.

/pdf/epitranscriptomic-regulation-of-the-response-to-the-air-1ajd8zn4y4.pdf

Epitranscriptomic regulation of the response to the air pollutant naphthalene in mouse lungs: From the perspectives of specialized translation and tolerance linked to the writer ALKBH8

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The epitranscriptomic writer ALKBH8 drives tolerance and protects mouse lungs from the environmental pollutant naphthalene.

Epitranscriptomic regulation of the response to the air pollutant naphthalene in mouse lungs: From the perspectives of specialized translation and tolerance linked to the writer ALKBH8