Crosstalk between m6A modification and alternative splicing during cancer progression

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(10)

Published: Oct. 1, 2023

Background N6-methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed demethylases and recognised m6A-binding proteins. This significantly influences carious facets of RNA metabolism plays a pivotal role cellular physiological processes. Main body Pre-mRNA alternative splicing, process that generates multiple splice isoforms from multi-exon genes, contributes to protein diversity mammals. Moreover, presence crosstalk between with modifications on pre-mRNAs exerting regulatory control, has been established. The modulates splicing patterns recruiting specific RNA-binding proteins (RBPs) regulate or directly influencing interaction RBPs their target RNAs. Conversely, can impact deposition recognition mRNAs. integration expanded scope therapeutic strategies for cancer treatment, while offers novel insights into mechanistic methylation initiation progression. Conclusion review aims highlight biological functions machinery its implications tumourigenesis. Furthermore, we discuss clinical relevance understanding m6A-dependent tumour therapies.

Language: Английский

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Exercise training decreases lactylation and prevents myocardial ischemia–reperfusion injury by inhibiting YTHDF2

Basic Research in Cardiology, Journal Year: 2024, Volume and Issue: 119(4), P. 651 - 671

Published: April 2, 2024

Language: Английский

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N6-methyladenosine modification is not a general trait of viral RNA genomes

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 11, 2024

Abstract Despite the nuclear localization of m 6 A machinery, genomes multiple exclusively-cytoplasmic RNA viruses, such as chikungunya (CHIKV) and dengue (DENV), are reported to be extensively A-modified. However, these findings mostly based on A-Seq, an antibody-dependent technique with a high rate false positives. Here, we address presence in CHIKV DENV RNAs. For this, combine A-Seq antibody-independent SELECT nanopore direct sequencing techniques functional, molecular, mutagenesis studies. Following this comprehensive analysis, find no evidence modification or transcripts. Furthermore, depletion key components host machinery does not affect infection. Moreover, infection has effect machinery’s localization. Our results challenge prevailing notion that is general feature cytoplasmic viruses underscore importance validating modifications orthogonal approaches.

Language: Английский

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Charting the epitranscriptomic landscape across RNA biotypes using native RNA nanopore sequencing

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(2), P. 276 - 289

Published: Jan. 1, 2025

Language: Английский

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Emerging Roles of RNA Methylation in Development

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(23), P. 3417 - 3427

Published: Nov. 15, 2023

More than 170 different types of chemical modifications have been identified on diverse RNA, collectively known as the epitranscriptome. Among them, N6-methyladenine (m6A), 5-methylcytosine (m5C), N1-methyladenine (m1A), and N7-methylguanosine (m7G) ubiquitous post-transcriptional modification are widely involved in regulating metabolic processes such RNA degradation, translation, stability, export, mediating important physiological pathological stress regulation, immune response, development, tumorigenesis. Recently, regulatory role during developmental is getting more attention. Therefore, development low-input even single-cell high-resolution sequencing technologies crucial for exploration roles these biological events trace samples.This account focuses various processes. We describe distribution characteristics modifications, catalytic enzymes, binding proteins, technologies. dynamically reversible, which can be catalyzed by methyltransferases eliminated demethylases. m6A most abundant eukaryote mRNA, mainly concentrated near stop codon, involves metabolism regulation. m5C, another studied modification, has a organisms species, enriched regions downstream translation initiation sites broadly distributes across whole coding sequence (CDS) mammalian mRNAs. m1A, with lower abundance m6A, distributed types, locates 5' untranslated region (5'UTR) mRNA regulates translation. m7G, one common eukaryotes, at cap internal positions RNAs recently gained considerable attention.Thanks to technology, found regulate tumorigenic process, including tumor proliferation, invasion, metastasis modulating oncogenes suppressor genes, affect oocyte maturation embryonic through maternal zygotic genes. m5C related proteins participate plant growth, neural stem cell differentiation dependent manner. m1A also revealed m7G dysregulation neurodevelopmental disorders neurodegenerative diseases.Collectively, we summarized gradually exhibited methylation discussed possibility candidate biomarkers potential therapeutic targets. The technological anticipated major driving force expand our knowledge this field.

Language: Английский

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Quantification and mapping of RNA modifications

TrAC Trends in Analytical Chemistry, Journal Year: 2024, Volume and Issue: 172, P. 117606 - 117606

Published: Feb. 21, 2024

Language: Английский

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Adapting nanopore sequencing basecalling models for modification detection via incremental learning and anomaly detection

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 21, 2024

We leverage machine learning approaches to adapt nanopore sequencing basecallers for nucleotide modification detection. first apply the incremental (IL) technique improve basecalling of modification-rich sequences, which are usually high biological interest. With sequence backbones resolved, we further run anomaly detection (AD) on individual nucleotides determine their status. By this means, our pipeline promises single-molecule, single-nucleotide, and context-free modifications. benchmark using control oligos, it in densely-modified yeast tRNAs E.coli genomic DNAs, cross-species N6-methyladenosine (m6A) mammalian mRNAs, simultaneous N1-methyladenosine (m1A) m6A human mRNAs. Our IL-AD workflow is available at: https://github.com/wangziyuan66/IL-AD . Here authors detect RNA The resolve modification-disturbed basecalling, then use assess

Language: Английский

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Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 14, 2024

Abstract In the last decade, messenger ribonucleic acid (mRNA)-based drugs have gained great interest in both immunotherapy and non-immunogenic applications. This surge can be largely attributed to demonstration of distinct advantages offered by various mRNA molecules, alongside rapid advancements nucleic delivery systems. It is noteworthy that immunogenicity presents a double-edged sword. context immunotherapy, extra supplementation adjuvant generally required for induction robust immune responses. Conversely, non-immunotherapeutic scenarios, activation unwanted considering host tolerability high expression demand mRNA-encoded functional proteins. Herein, mainly focused on linear non-replicating mRNA, we overview preclinical clinical progress prospects medicines encompassing vaccines other therapeutics. We also highlight importance focusing host-specific variations, including age, gender, pathological condition, concurrent medication individual patient, maximized efficacy safety upon administration. Furthermore, deliberate potential challenges may encounter realm disease treatment, current endeavors improvement, as well application future advancements. Overall, this review aims present comprehensive understanding mRNA-based therapies while illuminating prospective development drugs.

Language: Английский

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Quantifying m⁶A and Ψ Modifications in the Transcriptome via Chemical-Assisted Approaches

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(21), P. 2980 - 2991

Published: Oct. 18, 2023

ConspectusSince the discovery of first chemically modified RNA nucleotide in 1951, more than 170 types chemical modifications have been characterized so far. Since reversible and dynamic nature N6-methyladenosine (m6A) mRNA modification, researchers identified about ten eukaryotic mRNA; together with on noncoding RNAs, term "epitranscriptome" has coined to describe ensemble various modifications. The past decade witnessed many novel molecular functions modifications, demonstrating their crucial roles gene expression regulation. As most abundant mRNA, study m6A Ψ facilitated by innovative high-throughput sequencing technologies, which can be based antibodies, enzymes, or chemistry. Among them, chemical-assisted methods utilize selective chemistry that discriminate versus unmodified nucleotides, enabling transcriptome-wide mapping functional studies.Our group developed several technologies investigate these epitranscriptomic marks including m6A, Ψ, m1A, m6Am. we recently two for absolute quantification transcriptome reactivity distinguish measure In GLORI, used glyoxal nitrite mediate efficient deamination regular adenosine, while remained unaffected, thereby unbiased detection single-base resolution modification. CeU-seq PRAISE, different achieve labeling Ψ. is an azido-derivatized carbodiimide compound, PRAISE utilizes unique activity bisulfite results formation ring-opening Ψ-bisulfite adduct quantitatively detects as 1–2 nt deletion signatures during sequencing. resulting base-resolution stoichiometric information expanded our understanding profiles transcriptome. particular, quantitative methylome critical characterizing instance, under environmental stress development. Additionally, greatly facilitate analysis characterization modification sites are important regulation, especially when one type may multiple even opposing within a specific transcript. Together, profiling provide stoichiometry information, regulatory modifications.In this Account, will focus group, review recent advances reactions detection, discuss challenges future opportunities

Language: Английский

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Incorporation of 5 methylcytidine alleviates innate immune response to self-amplifying RNA vaccine

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 1, 2023

Abstract In order to improve vaccine effectiveness and safety profile of existing synthetic RNA-based vaccines, we have developed a self-amplifying RNA (saRNA)-based expressing membrane-anchored receptor binding domain (RBD) SARS-CoV-2 S protein (S-RBD) demonstrated that minimal dose this saRNA elicits robust immune responses. Results from recent clinical trial with 5-methylcytidine (5mC) incorporating reduced vaccine-induced adverse effects while maintaining humoral study, investigate the mechanisms accounting for induction efficient innate adaptive responses attenuated induced by 5mC-incorporated saRNA. We show 5mC-incorporating platform leads prolonged expression antigen, type-I interferon (IFN-I), key driver reactogenicity, is in peripheral blood mononuclear cells (PBMCs), but not macrophages dendritic cells. Interestingly, find major cellular source IFN-I production PBMCs plasmacytoid (pDCs), which upon 5mC incorporation addition, demonstrate monocytes also play an important role amplifying proinflammatory Furthermore, detection mediated host cytosolic sensor, RIG-I. Importantly, candidate produced IgG against S-RBD injection mice, thus providing strong support potential use vaccines.

Language: Английский

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