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At least 19 recordsLinked to original sources

PubMed2024

Mass Spectrometry-Based Proteomics for Assessing Epitranscriptomic Regulations.

Epitranscriptomics is a rapidly evolving field that explores chemical modifications in RNA and how they contribute to dynamic and reversible regulations of gene expression. These modifications, for example, N6-methyladenosine (m6A), are crucial in various RNA metabolic processes, including splicing, stability, subcellular localization, and translation efficiency of mRNAs. Mass spectrometry-based proteomics has become an indispensable tool in unraveling the complexities of epitranscriptomics, offering high-throughput, precise protein identification, and accurate quantification of differential protein expression. Over the past two decades, advances in mass spectrometry, including the improvement of high-resolution mass spectrometers and innovative sample preparation methods, have allowed researchers to perform in-depth analyses of epitranscriptomic regulations. This review focuses on the applications of bottom-up proteomics in the field of epitranscriptomics, particularly in identifying and quantifying epitranscriptomic reader, writer, and eraser (RWE) proteins and in characterizing their functions, posttranslational modifications, and interactions with other proteins. Together, by leveraging modern proteomics, researchers can gain deep insights into the intricate regulatory networks of RNA modifications, advancing fundamental biology, and fostering potential therapeutic applications.

Proteomics↗

PubMed2026

Maternal immune activation perturbs the brain epitranscriptome.

Maternal immune activation (MIA) results in abnormal fetal neurodevelopment and an increased risk of neurodevelopmental disorders. Altered RNA translation has been implicated in the pathophysiology of MIA-associated neurodevelopmental deficits, but more precise mechanisms underlying disruption in RNA metabolism are lacking. Here, we characterize key components of the RNA epitranscriptomic machinery, which refers to the set of reversible chemical modifications on RNA molecules that influence RNA function, including translation, stability, splicing, and localization. Using spatial transcriptomics, we define cell type- and brain region-specific distribution of epitranscriptome regulators in the developing mouse brain. We also use direct RNA sequencing to define how MIA changes the brain epitranscriptome landscape. We identify the demethylase FTO as being notably perturbed in the context of MIA. Using pharmacological and genetic approaches, we target FTO to ameliorate behavioral phenotypes in MIA offspring. In total, this work expands upon mechanisms of translational misregulation in MIA and identifies new targets for therapeutic manipulation.

Animals↗

PubMed2026

How Epitranscriptomic Machinery Senses Environmental Cues.

Environmental fluctuations remodel RNA modification landscapes, yet the routes that connect cue detection to writer-eraser-reader control remain dispersed across disciplines. Here, we consolidate upstream mechanisms capable of driving epitranscriptomic change and organize them by response speed. At the fastest proximal level, catalytic output can be modulated through shifts in substrate and cofactor availability, redox and ionic state, temperature, and direct chemical or metal interference with enzyme active sites, although transcriptome-wide RNA readouts may appear later. Over minutes to hours, cue-responsive signaling can reach the machinery through post-translational modification, partner switching, subcellular trafficking, and stress-induced condensates that may gate access to modified transcripts. Across hours to days, regulator abundance and specificity are reshaped by transcriptional programs, translational control, and protein quality-control pathways, enabling adaptation and, in some contexts, persistence. We propose a kinetics-to-sensors approach for interpreting time-resolved epitranscriptomic datasets and prioritizing perturbations that discriminate among candidate upstream inputs. We also outline conceptual gaps and experimental practices needed to establish causal cue-to-mark chains.

Epitranscriptome↗

PubMed2026

m6A-Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration.

Mitochondrial dysfunction is a common pathology of neurodegenerative diseases, which contributes to neuronal vulnerability via excessive oxidative stress, impaired bioenergetics, and dysregulated apoptosis. Emerging studies highlighted the critical role of epitranscriptomic RNA modifications, particularly N6-methyladenosine (m6A), in mitochondrial gene expression regulation and cellular stress responses. m6A modifications are installed by methyltransferases ("writers," METTL3/METTL14), recognized by reader proteins (YTH domain family proteins, IGF2BPs), and removed by demethylases ("erasers," FTO, ALKBH5), collectively orchestrating mRNA splicing, localization, stability, and translation. Recent evidence demonstrates that m6A modifications modulate both nuclear-encoded and mitochondrially encoded transcripts and regulate key mitochondrial processes, including fission/fusion dynamics, oxidative phosphorylation, mitophagy, and apoptosis. Dysregulation of m6A machinery disrupts mitochondrial homeostasis, exacerbates oxidative stress and neuroinflammation, and promotes neuronal loss. Importantly, pharmacological or genetic modulation of m6A regulators can restore mitochondrial function, inhibit caspase activation, and dampen pro-inflammatory signaling, underscoring their therapeutic potential. This review consolidates current insights into mitochondrial epitranscriptomics, emphasizing how m6A modifications act as central regulators of mitochondrial stress responses and neurodegeneration.

Humans↗

PubMed2026

Oxidative stress-driven epigenetic reprogramming of immune cells in COPD: from epitranscriptomic and metabolic crosstalk to treatable traits.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by persistent oxidative stress and maladaptive immune responses, rather than a single disease entity. Oxidative stress not only damages lung tissue but also reprograms immune cells through both classical epigenetic mechanisms (DNA methylation, histone modifications) and epitranscriptomic regulation (m6A RNA methylation), shaping disease endotypes and treatment resistance. This review presents an integrated framework in which redox signals dynamically reshape the epigenetic and epitranscriptomic landscape, thereby locking immune cells into pathogenic states. Metabolic intermediates (S-adenosylmethionine, α-ketoglutarate, succinate, NAD+) serve as critical nodes that connect immunometabolism to both classical epigenetic enzymes and the m6A machinery, thereby linking redox status to RNA fate. Using NETosis as a paradigm, we illustrate how oxidative-epigenetic-metabolic loops sustain neutrophilic inflammation and resolution failure. Finally, we outline a treatable traits framework that integrates these mechanistic insights into precision combination therapies. This conceptual roadmap aims to shift COPD management from symptom control toward durable, mechanism-driven disease modification.

Humans↗

PubMed2026

The pseudouridine epitranscriptomic landscape of advanced prostate cancer therapeutic resistance identifies TIMM17A as a key player.

BACKGROUND: Resistance to androgen receptor signaling inhibitors (ARSIs) remains a major barrier of advanced prostate cancer (PCa) treatment. While RNA epitranscriptomic modifications are increasingly recognized as key regulators of tumor biology, the role of pseudouridine (Ψ) in therapeutic resistance is largely unexplored. METHODS: A darolutamide-resistant PCa cell model was established and subjected to integrated multi-omics profiling using bulk RNA sequencing and photo-crosslinking-assisted Ψ sequencing (PA-Ψ-seq). Differential expression and pseudouridylation analyses were combined to identify Ψ-associated genes. Public datasets validated expression and prognosis. Functional assays including RNA knockdown, cell proliferation, colony formation, and xenograft models were conducted. Single-cell RNA sequencing investigated tumor microenvironment (TME) interactions. RESULTS: We identified extensive transcriptomic and pseudouridylation alterations associated with ARSI resistance, with a significant positive correlation between Ψ modification and mRNA expression. Integrated analysis highlighted a subset of "hyper-up" genes enriched in resistance-related pathways. Thus, TIMM17A was identified as a novel candidate. TIMM17A expression was significantly elevated in PCa and correlated with disease progression and poor prognosis. Experimental validations demonstrated that TIMM17A promoted tumor growth and resistance, while its knockdown restored sensitivity to darolutamide both in vitro and in vivo. Mechanistically, TIMM17A expression may be regulated by PUS1‑mediated pseudouridylation. Single-cell analysis further revealed that TIMM17A is enriched in malignant epithelial cells and associated with enhanced cell-cell communication within the TME. CONCLUSIONS: This study delineates the pseudouridine epitranscriptomic landscape in advanced PCa and identifies TIMM17A as a key mediator of therapeutic resistance. Targeting the Ψ-TIMM17A axis may offer a novel strategy to overcome ARSI resistance.

Advanced prostate cancer↗

PubMed2026

Epitranscriptomic erasers in bivalves: Evolutionary divergence and species-specific transcriptional plasticity of the ALKBH family under acute thermal stress.

The AlkB homolog (ALKBH) family of Fe(II)/α-ketoglutarate-dependent dioxygenases mediates nucleic acid demethylation, thereby governing RNA metabolism and genomic stability. Despite their pivotal roles in epitranscriptomic regulation across vertebrates, the evolutionary dynamics and functional significance of ALKBH proteins in bivalve mollusks remain largely unexplored. Here, we present a comprehensive phylogenomic analysis of 210 ALKBH genes identified across 35 bivalve species. Our analyses reveal a distinct evolutionary trajectory characterized by the lineage-specific loss of ALKBH4 and the restricted distribution of ALKBH5 to the Mytilidae family, contrasting sharply with vertebrate repertoires. Using the noble scallop (Chlamys nobilis) and Pacific oyster (Crassostrea gigas) as model systems, we demonstrate that ALKBH genes exhibit conserved spatiotemporal expression patterns, with pronounced enrichment in gonadal tissues and during metamorphic transitions, implicating these enzymes in gametogenesis and larval development. Furthermore, comparative thermal stress experiments reveal divergent transcriptional plasticity: the subtropical scallop C. nobilis mounts rapid, transient induction of ALKBH1/2/6 under heat shock, whereas the eurythermal oyster C. gigas maintains sustained ALKBH3 expression, potentially underpinning its superior thermal tolerance. Conversely, cold stress elicits bimodal regulation in C. nobilis, with ALKBH1/2 upregulation contrasting with ALKBH6/7/8 suppression. These findings illuminate the functional diversification of bivalve ALKBH genes and their potential utility as molecular biomarkers for assessing developmental competence and thermal resilience in shellfish aquaculture.

Animals↗

PubMed2026

Epigenetic-epitranscriptomic crosstalk through TaHAG1-TaNSUN2 coordinates thermotolerance in wheat.

High temperature is a primary abiotic stress that severely constrains crop productivity. Deciphering the regulatory pathways underlying heat responses is essential for breeding heat-tolerant crops with stable yields. Although both epigenetic and epitranscriptomic regulations are involved in plant heat adaptation, their mechanistic interplay remains unclear. Here, integrated epigenomic (H3K9Ac/H3K14Ac) and transcriptomic profiling under heat stress identifies the mRNA m⁵C methyltransferase TaNSUN2 as a key regulator of thermotolerance in wheat. We demonstrate that TaNSUN2 is transcriptionally activated by the histone acetyltransferase TaHAG1, which deposits H3K9Ac at the TaNSUN2 promoter and transcription start site. This recruitment is facilitated by the transcription factors TaE2F1 and TaDP1, which interact with TaHAG1 to form a functional complex. Functional assays revealthat TaNSUN2 operates downstream of TaHAG1 and enhances thermotolerance through m⁵C‑dependent mRNA methylation and stabilization of transcripts involved in chloroplast organization. Furthermore, field trials show that TaNSUN2-overexpressing lines exhibit higher grain yield under normal conditions and reduced yield loss under heat stress. Our findings elucidate an integrated regulatory network linking histone acetylation to RNA m⁵C methylation in heat stress adaptation, providing promising targets for molecular breeding of heat‑resilient wheat.

Triticum↗

PubMed2024

Epitranscriptomic cytidine methylation of the hepatitis B viral RNA is essential for viral reverse transcription and particle production.

Epitranscriptomic RNA modifications have emerged as important regulators of the fate and function of viral RNAs. One prominent modification, the cytidine methylation 5-methylcytidine (m5C), is found on the RNA of HIV-1, where m5C enhances the translation of HIV-1 RNA. However, whether m5C functionally enhances the RNA of other pathogenic viruses remains elusive. Here, we surveyed a panel of commonly found RNA modifications on the RNA of hepatitis B virus (HBV) and found that HBV RNA is enriched with m5C as well as ten other modifications, at stoichiometries much higher than host messenger RNA (mRNA). Intriguingly, m5C is mostly found on the epsilon hairpin, an RNA element required for viral RNA encapsidation and reverse transcription, with these m5C mainly deposited by the cellular methyltransferase NSUN2. Loss of m5C from HBV RNA due to NSUN2 depletion resulted in a partial decrease in viral core protein (HBc) production, accompanied by a near-complete loss of the reverse transcribed viral DNA. Similarly, mutations introduced to remove the methylated cytidines resulted in a loss of HBc production and reverse transcription. Furthermore, pharmacological disruption of m5C deposition led to a significant decrease in HBV replication. Thus, our data indicate m5C methylations as a critical mediator of the epsilon elements' function in HBV virion production and reverse transcription, suggesting the therapeutic potential of targeting the m5C methyltransfer process on HBV epsilon as an antiviral strategy.

Hepatitis B virus↗

PubMed2025

Epitranscriptomic reprogramming in response to low CO2 stress and m6A engineering to enhance biomass production in Nannochloropsis oceanica.

N6-adenine methylation (m6A) as an epitranscriptomic mark is the most abundant modification in eukaryotic RNA and plays a dynamically regulated role. However, m6A dynamics, deposition and engineering in microalgae remain largely unknown. Here, in Nannochloropsis oceanica, the dynamic alterations and reprogramming in m6A RNA modifications after the shift from high to low CO2 conditions were first investigated using methylated RNA immunoprecipitation sequencing. The m6A peaks in N. oceanica were mainly enriched in 3'UTR. A positive association between m6A abundance and mRNA transcription of CO2-responsive genes was observed; moreover, N. oceanica cells adopted versatile strategies in a dynamic reprogramming of m6A in response to low CO2 stress. Secondly, knockout of two putative m6A methylases including NoMTA (NO04G02990) and NoMTB (NO07G02450) by genome editing induced methylation reprogramming, which was associated with expression changes of low-CO2 responsive genes such as carbon/nitrogen metabolism, and photorespiration genes that underlie reductions in growth and biomass. Lastly, m6A modification reprogramming was first engineered to increase low-CO2 stress tolerance and biomass productivity by the CRISPR/dCas13 system combined with MTA and NoMTB under low CO2 in N. oceanica. Therefore, these strides would pave the way for microalgal epigenetics and future industrial applications.

Microalgae↗

PubMed2026

Epitranscriptomic Regulation of ALDOA by SHMT2-Mediated m6A Modification Drives Gastric Cancer Malignancy.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic advancements despite progress in early detection. Serine hydroxymethyltransferase 2 (SHMT2), a key metabolic enzyme, and fructose-1,6-bisphosphate aldolase A (ALDOA), a glycolytic enzyme, are implicated in tumor progression. However, the molecular mechanisms linking SHMT2 and ALDOA in GC remain unclear. This study investigates how SHMT2 regulates ALDOA expression via m6A RNA modification to drive GC malignancy. Bioinformatic analyses (TCGA, LinkedOmics, and SRAMP) were used to assess SHMT2 expression in GC patients and identify its correlated genes. In vitro experiments (CCK-8, EdU, Transwell, and wound healing) evaluated the effects of SHMT2 overexpression or knockdown on GC cell proliferation, migration, invasion, and glycolysis. m6A modification of ALDOA was analyzed via MeRIP-PCR and dual-luciferase assays, while RNA stability was assessed using actinomycin D treatment. Xenograft models validated SHMT2's role in vivo. SHMT2 was upregulated in GC tissues and cell lines, correlating with advanced tumor stages and poor prognosis. SHMT2 knockdown suppressed GC cell viability, migration, invasion, and glycolysis, while overexpression enhanced these traits. Mechanistically, SHMT2 increased S-adenosylmethionine levels, promoting ALDOA m6A modification, likely mediated through the predicted site 1 (position 291). This modification stabilized ALDOA mRNA via IGF2BP1 recognition, an m6A reader. ALDOA overexpression reversed the tumor-suppressive effects of SHMT2 knockdown. In vivo, SHMT2 depletion reduced tumor growth and Ki67 expression in xenograft models. In conclusion, SHMT2 drives GC progression by enhancing ALDOA expression through m6A modification and IGF2BP1-mediated stabilization. Targeting the SHMT2-ALDOA axis represents a promising therapeutic strategy for gastric cancer.

Humans↗

PubMed2026

Functional Prediction of Epitranscriptome.

N6-methyladenosine (m6A) is one of the most prevalent and well-studied RNA modifications, playing a pivotal role in many biological processes. With the recent advances in high-throughput sequencing technologies, tens of thousands of m6A sites have been reported. However, not all m6A sites are important or functionally significant, highlighting the need to distinguish biologically relevant m6As from non-functional or technically artefactual ones. Here, we describe ConsRM, which is a web-based resource that was designed to evaluate the importance of m6As from an evolutionary perspective. It introduced a novel scoring framework for quantifying the conservation degree of m6As in humans. Its web interface includes a database of 177998 distinct human m6A sites along with their calculated conservation score, and allows users to analyze their own data via the web server. ConsRM is freely accessible at: http://180.208.58.19/conservation/browser.html .

Humans↗

PubMed2026

tRNA methylation: functional insights and epitranscriptomic regulation.

tRNAs, one of the most conserved and abundant RNAs, are central components of protein synthesis, transferring genetic information from DNA to proteins through a precise base-pairing mechanism. Post-transcriptional modifications of tRNAs by tRNA modifying enzymes are essential for maintaining their normal physiological functions, including methylation, isomerization and glycosylation. tRNA methylation, particularly 1-methyladenosine (m1A), 5-methylcytidine (m5C), and 7-methylguanosine (m7G), are among the most abundant and diverse types of post-transcriptional modifications of tRNA, which promote the stability of tRNA secondary and tertiary structures and allow for proper translation. In addition, tRNA methylation affects the production and function of tsRNA (tRNA-derived small RNA), small fragments of RNA that further regulate gene expression and protein synthesis. In our review, we discuss the relevant biological functions of tRNA methylation, including tRNA stability, protein translation, and tsRNA biogenesis.

RNA, Transfer↗

PubMed2026

Phosphate backbone epitranscriptomics: Discovery of natural RNA phosphorothioates and their writer machinery.

Over 150 modifications expand the RNA alphabet, yet all known natural modifications occur on nucleobases or ribose sugars, with none identified on the phosphate backbone. In contrast, phosphorothioates (PSs), in which a non-bridging phosphate oxygen is replaced with sulfur, are central to RNA therapeutics but have never been reliably detected in natural RNAs. Here, we develop sequencing- and mass spectrometry-based approaches to quantitatively map RNA PSs at single-nucleotide resolution. Across diverse archaeal species, we identify stereospecific PS modifications at rRNA and tRNA hotspots, which are dynamically regulated by sulfur availability and temperature. We uncover a diverse enzyme family that selectively modifies tRNA/rRNA substrates and whose evolutionary presence/absence matches the distribution of PSs. Enzyme loss causes inviability or temperature sensitivity, and functional analyses reveal that tRNA PSs enhance tRNA stability. These findings establish the first natural RNA phosphate-backbone modification and its enzymatic machinery, providing a foundation for mechanistic and functional exploration.

RNA modifications↗

PubMed2024

Crosstalk between epitranscriptomic and epigenomic modifications and its implication in human diseases.

Crosstalk between N6-methyladenosine (m6A) and epigenomes is crucial for gene regulation, but its regulatory directionality and disease significance remain unclear. Here, we utilize quantitative trait loci (QTLs) as genetic instruments to delineate directional maps of crosstalk between m6A and two epigenomic traits, DNA methylation (DNAme) and H3K27ac. We identify 47 m6A-to-H3K27ac and 4,733 m6A-to-DNAme and, in the reverse direction, 106 H3K27ac-to-m6A and 61,775 DNAme-to-m6A regulatory loci, with differential genomic location preference observed for different regulatory directions. Integrating these maps with complex diseases, we prioritize 20 genome-wide association study (GWAS) loci for neuroticism, depression, and narcolepsy in brain; 1,767 variants for asthma and expiratory flow traits in lung; and 249 for coronary artery disease, blood pressure, and pulse rate in muscle. This study establishes disease regulatory paths, such as rs3768410-DNAme-m6A-asthma and rs56104944-m6A-DNAme-hypertension, uncovering locus-specific crosstalk between m6A and epigenomic layers and offering insights into regulatory circuits underlying human diseases.

Humans↗

PubMed2026

PRRSV suppresses FTO-dependent m6A demethylation to reprogram STAT signaling and innate immunity.

RNA viruses have evolved diverse strategies to evade host interferon (IFN)-stimulated gene (ISG) defenses; however, how they exploit host epitranscriptomic regulation remains poorly understood. Here, we identify an immune-evasion mechanism in which porcine reproductive and respiratory syndrome virus (PRRSV) targets the m6A demethylase fat mass and obesity-associated protein (FTO) to suppress antiviral signaling. Mechanistically, the viral endoribonuclease nsp11 inhibits STAT5-dependent transcription through the key residues Q96 and S104, thereby reducing FTO expression. Loss of FTO increases m6A modification of STAT2 and STAT3 transcripts, impairing their translation and phosphorylation, thereby attenuating ISG responses. Reduced STAT3 activity further dampens STAT5 signaling, establishing a feed-forward circuit that amplifies suppression of antiviral immunity. Functionally, disruption of this regulatory region (Q96A and S104A) attenuates viral pathogenicity in vivo and restores ISG induction. These mutations also reduce infection-associated inflammatory responses and the accumulation of reactive oxygen species. Together, these findings define a nsp11-STAT5-FTO-STAT2/3 axis that enables PRRSV to reprogram host epitranscriptomic control of innate immunity. Our work reveals a mechanism of epitranscriptomic hijacking and identifies FTO as a key host factor exploited by RNA viruses, highlighting m6A regulation as a potential target for antiviral intervention.IMPORTANCEViruses must overcome host innate immune defenses to establish infection; however, the mechanisms by which they manipulate host RNA regulation remain incompletely understood. In this study, we show that porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon responses by targeting the host m6A demethylase FTO through its endoribonuclease nsp11. This process involves the inhibition of STAT5 phosphorylation, which reduces FTO expression and increases m6A modification of key immune regulators, including STAT2 and STAT3, thereby impairing their activation. Disruption of this pathway attenuates viral pathogenicity in vivo and restores antiviral signaling. These results demonstrate that PRRSV can reprogram host epitranscriptomic regulation to modulate innate immunity and suggest that m6A-related pathways may be potential targets for antiviral intervention.

Immunity, Innate↗

PubMed2026

Integrated multi-omics analysis reveals a pH-driven metabolic and translational switch in Ureaplasma parvum.

Human ureaplasmas are minimal-genome bacteria and pathobionts of the urogenital tract. They must adapt to fluctuating pH conditions despite the absence of canonical transcriptional regulatory systems. However, the mechanisms underlying these responses remain unclear. This study aimed to construct a system-level model of pH adaptation in this minimal pathogen. We used an integrated multi-omics platform combining proteomics, metabolomics, and RNA modification profiling to construct a system-level model of pH adaptation. The results revealed a bifurcated strategy governed by the differential activation of preexisting, co-regulated functional modules. Under neutral pH conditions (pH 7), Ureaplasma parvum activated energy metabolism and upregulated ATP synthesis while forming a stress-counteracting proteostasis pathway. This may suggest a biological energy state under high stress conditions. Conversely, under acidic stress (pH 5), it activated biosynthesis/translation, showing significant upregulation of ribosomal proteins and accumulation of translation precursors and the polyamine spermidine. This may represent a state of expanded translational capacity. This adaptive switch is accompanied by dynamic reorganization of the epitranscriptome, highlighting the importance of post-transcriptional regulation. This study suggests mechanisms by which minimal organisms achieve adaptive plasticity through sophisticated post-transcriptional and metabolic control, providing a new framework for understanding Ureaplasma physiology and the biology of genome-reduced organisms.IMPORTANCEMinimal bacteria challenge canonical views of cellular regulation. In organisms with radically reduced genomes and sparse transcription factors, how adaptive plasticity is achieved remains a core question. Our study proposes a model in which a simple physicochemical cue-extracellular pH-selects among prewired cellular programs, while post-transcriptional and epitranscriptomic layers fine-tune execution. The findings of this study suggest a multi-omics scheme for how organisms adapt to environmental changes and ensure survival without inducing new circuits or complex transcriptional regulation. Conceptually, it proposes regulation via RNA modifications in processes, such as metabolism, proteostasis, and translation. This framework may be generalizable to other genome-reduced microorganisms. Beyond microbiology, it provides design principles for synthetic biology and offers a mechanistic interpretation of phenotypic tolerance to stress factors. It may encourage the use of pH-linked epitranscriptome signals as measurable indicators of cellular state.

Hydrogen-Ion Concentration↗

PubMed2026

Translational reprogramming of TGF-β signaling via TRMT61A-mediated tRNA m1A drives prostatic fibrosis and hyperplasia.

Dysregulation of the epitranscriptomic landscape is closely linked to pathological proliferation, but its specific role in benign prostatic hyperplasia (BPH) remains unclear. Here, we identify the tRNA methyltransferase TRMT61A as a critical driver of BPH progression. We found that TRMT61A and global N1-methyladenosine (m1A) levels are aberrantly upregulated in human BPH tissues. Functionally, TRMT61A knockdown potently suppresses prostate cell proliferation and reduces stromal fibrosis, inducing G1 cell cycle arrest and reversing pathological remodeling both in vitro and in vivo. By integrating ribosome profiling (Ribo-seq) and tRNA-seq, we observed that TRMT61A drives translational reprogramming. TRMT61A preserves the stability of specific tRNA isoacceptors (e.g., tRNA-Leu-CAA), which is required for the efficient decoding of mRNAs containing m1A-dependent codons. Consequently, TRMT61A selectively promotes the translational elongation of the key receptor TGFβR1. This amplifies downstream TGF-β/SMAD signaling and drives epithelial-mesenchymal transition (EMT) without affecting mRNA transcription. In summary, our study reveals how TRMT61A drives BPH progression through TGFβR1 translation, highlighting the therapeutic potential of targeting epitranscriptomic pathways to reverse prostatic hyperplasia and fibrosis.

Male↗