Explore the vast range of titles available.

5-methylcytosine (m⁵C) is an important epitranscriptomic modification involved in messenger RNA (mRNA) stability and translation efficiency in various biological processes. However, it remains unclear if m⁵C modification contributes to the dynamic regulation of the transcriptome during the developmental cycles of Plasmodium parasites. Here, we characterize the landscape of m⁵C mRNA modifications at single nucleotide resolution in the asexual replication stages and gametocyte sexual stages of rodent (Plasmodium yoelii) and human (Plasmodium falciparum) malaria parasites. While different representations of m⁵C-modified mRNAs are associated with the different stages, the abundance of the m⁵C marker is strikingly enhanced in the transcriptomes of gametocytes. Our results show that m⁵C modifications confer stability to the Plasmodium transcripts and that a Plasmodium ortholog of NSUN2 is a major mRNA m⁵C methyltransferase in malaria parasites. Upon knockout of P. yoelii nsun2 (pynsun2), marked reductions of m⁵C modification were observed in a panel of gametocytogenesis-associated transcripts. These reductions correlated with impaired gametocyte production in the knockout rodent malaria parasites. Restoration of the nsun2 gene in the knockout parasites rescued the gametocyte production phenotype as well as m⁵C modification of the gametocytogenesis-associated transcripts. Together with the mRNA m⁵C profiles for two species of Plasmodium, our findings demonstrate a major role for NSUN2-mediated m⁵C modifications in mRNA transcript stability and sexual differentiation in malaria parasites.

Interferon‐stimulated gene 20 kDa protein (ISG20) is a relatively understudied antiviral protein capable of inhibiting a broad spectrum of viruses. ISG20 exhibits strong RNase properties, and it belongs to the large family of DEDD exonucleases, present in both prokaryotes and eukaryotes. ISG20 was initially characterized as having strong RNase activity in vitro, suggesting that its inhibitory effects are mediated via direct degradation of viral RNAs. This mechanism of action has since been further elucidated and additional antiviral activities of ISG20 highlighted, including direct degradation of deaminated viral DNA and translational inhibition of viral RNA and nonself RNAs. This review focuses on the current understanding of the main molecular mechanisms of viral inhibition by ISG20 and discusses the latest developments on the features that govern specificity or resistance to its action. ISG20 is a broad antiviral inhibitor and a potent RNase in vitro. However, a precise understanding of its mechanism of action is lacking. In this review, we discuss the latest developments on this fascinating innate defense factor.

Internal modifications of mammalian RNA have been suggested to be essential for the maintenance of cardiac homeostasis. However, the role of RNA cytosine methylation (m5C) in the heart remains largely unknown. Bulk and single cell RNA sequencing data and tissues from the human hearts were exploited for analyzing the expression of RNA m5C modifying proteins. Neonatal rat and adult mouse cardiomyocytes were isolated to assess the impact of Nsun2 on cellular hypertrophic response. Cre/LoxP-mediated gene knockout and recombinant adeno-associated virus serotype 9 (rAAV9) were employed respectively to achieve cardiac-specific interference of the expression of related genes in mice that were subjected to heart stresses from aging, aortic constriction, and angiotensin II stimulation. RNA m5C immunoprecipitation sequencing (m5C-RIP-seq), RNA pull-down, polysome profiling, reporter gene analysis, and IonOptix measurement were conducted to elucidate the involved regulatory mechanisms. Nsun2 expression was significantly elevated in human, rat, and mouse hypertrophic myocardial cells. Knockout of Nsun2 (αMHC-Cre , Nsun2 flox ) abolished the hypertrophic response of mice to diverse stresses, while accelerating the progression of heart failure. Mechanistically, Nsun2 specifically methylates PKA catalytic subunit alpha (PRKACA) mRNA, which substantially promotes PRKACA translation in a YBX1-dependent manner. Nsun2 ablation markedly attenuated the activation of PKA signaling, as evidenced by the reduced PKA activity and protein phosphorylation levels of PKA substrates, impaired myocyte contraction and relaxation, and disturbed calcium transients. Overexpressing Nsun2 and PRKACA-3'UTR transcripts in the myocardia sensitized and desensitized heart hypertrophic responses, respectively, whereas co-administration of the PKA inhibitor H-89 or overexpressing PRKACA-3'UTR transcript lacking Nsun2 methylating regions failed to produce corresponding responses, reiterating the significance of Nsun2-PRKACA regulation in the cardiac hypertrophic program. These observations reveal the importance of Nsun2-PRKACA regulation in cardiac homeostasis, which provides novel insights into heart function modulation and sheds light on future treatments for hypertrophic remodeling associated heart diseases.

N6-methyladenosine (m 6 A) modification of messenger RNA (mRNA) is the most prevalent and abundant modification in eukaryotic mRNA and posttranscriptionally modulates the transcriptome at almost all stages of mRNA metabolism. In plants, m 6 A is crucial for embryonic-phase growth, flowering time control, microspore generation and fruit maturation. However, the role of m 6 A in plant responses to light, the most important environmental stimulus, remains unexplored. Here, we profile the m 6 A transcriptome of Williams 82, a soybean cultivar, and reveal that m 6 A is highly conserved and plays an important role in the response to light stimuli in soybean. Similar to the case in Arabidopsis , m 6 A in soybean is enriched not only around the stop codon and within the 3’UTR but also around the start codon. Moreover, genes with methylation occurring in the 3’UTR have higher expression levels and are more prone to alternative splicing. The core genes in the light signaling pathway, GmSPA1a , GmPRR5e and GmBIC2b , undergo changes in methylation modification and transcription levels in response to light. KEGG pathway analysis revealed that differentially expressed genes with differential m 6 A peaks were involved in the “photosynthesis” and “circadian rhythm” pathways. Our results highlight the important role played by epitranscriptomic mRNA methylation in the light response in soybean and provide a solid basis for determining the functional role of light on RNA m 6 A modification in this plant.

Epitranscriptomic modifications, as a dynamic and reversible system of chemical modifications, have emerged as a key regulatory hub for programmed cell death (PCD) by finely modulating the RNA metabolic network. During the pathological progression of liver diseases, aberrant alterations in epitranscriptomic modifications can disrupt the dynamic equilibrium of PCD signaling pathways, leading to excessive cell death or abnormal survival of hepatocytes, thereby driving the development of metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, alcohol-associated liver disease (ALD), hepatic fibrosis, and hepatocellular carcinoma (HCC). A thorough investigation into the molecular mechanisms of epitranscriptomic modifications in PCD pathways and their roles in liver diseases not only aids in elucidating the pathogenesis of liver disorders but also holds the potential to provide new biomarkers and therapeutic targets for the diagnosis, prognosis, and treatment of liver diseases. This review systematically summarizes the molecular mechanisms of epitranscriptomic modifications, delves into the complex regulatory networks between epitranscriptomic modifications and PCD, elaborates on their roles in liver diseases, and provides a comprehensive overview of current drugs targeting epitranscriptomic modifications. These insights offer new treatment ideas for liver diseases and new directions for precision medicine research.

Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) is an RNA binding protein that functions as an N6-methyladenosine reader. It regulates various biological processes in human cancers by affecting the stability and expression of target RNA transcripts, including coding RNAs and non-coding RNAs (ncRNAs). Numerous studies have shown that IGF2BP2 expression is aberrantly increased in various types of cancer and plays multifaceted roles in the development and progression of human cancers. In the present review, the clinical importance of IGF2BP2 is summarized and its involvement in the regulation of biological processes, including proliferation, metastasis, chemoresistance, metabolism, tumor immunity, stemness and cell death, in human cancers is discussed. The chemical compounds that have been developed as IGF2BP2 inhibitors are also detailed. As ncRNAs are now important potential therapeutic agents for cancer treatment, the microRNAs that have been reported to directly target and inhibit IGF2BP2 expression in cancers are also described. In summary, by reviewing the latest literature, the present study aimed to highlight the clinical importance and physiological functions of IGF2BP2 in human cancer, with a focus on the great potential of IGF2BP2 as a target for inhibitor development. The present review may inspire new ideas for future studies on IGF2BP2, which may serve as a specific therapeutic target in cancer.

The molecular mechanisms that regulate stem cell pluripotency and differentiation has shown the crucial role that methylation plays in this process. DNA methylation has been shown to be important in the context of developmental pathways, and the role of histone methylation in establishment of the bivalent state of genes is equally important. Recent studies have shed light on the role of RNA methylation changes in stem cell biology. The dynamicity of these methylation changes not only regulates the effective maintenance of pluripotency or differentiation, but also provides an amenable platform for perturbation by cellular stress pathways that are inherent in immune responses such as inflammation or oncogenic programs involving cancer stem cells. We summarize the recent research on the role of methylation dynamics and how it is reset during differentiation and de-differentiation.

Epitranscriptomic RNA modifications play a crucial role in the posttranscriptional regulation of gene expression. N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic RNA and plays a pivotal role in RNA fate. RNA m6A modification is regulated by a group of cellular proteins, methyltransferases (writers) and demethylases (erasers), which add and remove the methyl group from adenosine, respectively. m6A modification is recognized by a group of cellular RNA-binding proteins (readers) that specifically bind to m6A-modified RNA, mediating effects on RNA stability, splicing, transport, and translation. The functional significance of m6A modification of viral and cellular RNA is an active area of virology research. In this review, we summarize and analyze the current literature on m6A modification of HIV-1 RNA, the multifaceted functions of m6A in regulating HIV-1 replication, and the role of viral RNA m6A modification in evading innate immune responses to infection. Furthermore, we briefly discuss the future directions and therapeutic implications of mechanistic studies of HIV-1 epitranscriptomic modifications.

Over 17 and 160 types of chemical modifications have been identified in DNA and RNA, respectively. The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edged fields of epigenomics and epitranscriptomics. Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study. Here, we review the recent technological advances in this rapidly evolving field. We focus on high-throughput detection methods and biological findings for these modifications, and discuss questions to be addressed as well. We also summarize third-generation sequencing methods, which enable long-read and single-molecule sequencing of DNA and RNA modification.