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N1-methyladenosine (m1A) is a reversible epigenetic modification of RNAs. Aberrant m1A modification levels due to dysregulation of m1A regulators have been observed in multiple cancers. tRNA methyltransferase 10C (TRMT10C) can install m1A in RNAs; however, its role in hepatoblastoma remains unknown. We conducted this study to identify causal polymorphisms in the TRMT10C gene for hepatoblastoma susceptibility in a cohort of Chinese children (313 cases vs. 1446 controls). The genotypes of four potential functional polymorphisms (rs7641261 C>T, rs2303476 T>C, rs4257518 A>G, and rs3762735 C>G) were determined in participants using TaqMan real-time PCR. The associations of these polymorphisms with hepatoblastoma susceptibility were estimated by logistic regression analysis adjusted for age and sex. All four polymorphisms were significantly associated with hepatoblastoma risk. In particular, under the recessive genetic model, these polymorphisms conferred an increased risk of hepatoblastoma: rs7641261 C>T [adjusted odds ratio (OR)=1.64, 95% confidence interval (CI)=1.04-2.58, P=0.033], rs2303476 T>C (adjusted OR=1.87, 95% CI=1.16-3.02, P=0.010), rs4257518 A>G (adjusted OR=1.45, 95% CI=1.09-1.94, P=0.012), and rs3762735 C>G (adjusted OR=3.83, 95% CI=2.15-6.82, P<0.0001). Combined analysis revealed that kids had an increased risk of developing hepatoblastoma if they harbored at least one risk genotype (adjusted OR=1.94, 95% CI=1.48-2.54, P<0.0001). In addition, the combined risk effects of the four SNPs persisted across all the subgroups. We identified four hepatoblastoma susceptibility loci in the TRMT10C gene. Identifying more disease-causing loci may facilitate the development of genetic marker panels to predict individuals' hepatoblastoma predisposition.

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Hepatoblastoma, the most frequently diagnosed primary paediatric liver tumour, bears the lowest somatic mutation burden among paediatric neoplasms. Therefore, it is essential to identify pathogenic germline genetic variants, especially those in oncogenic genes, for this disease. The tRNA methyltransferase 6 noncatalytic subunit (TRMT6) forms a tRNA methyltransferase complex with TRMT61A to catalyse adenosine methylation at position N1 of RNAs. TRMT6 has displayed tumour-promoting functions in several cancer types. However, the contribution of its genetic variants to hepatoblastoma remains unclear. In this study, we investigated the association between four TRMT6 polymorphisms (rs236170 A > G, rs451571 T > C, rs236188 G > A and rs236110 C > A) and the risk of hepatoblastoma in a cohort of 313 cases and 1446 healthy controls. Germline DNA was subjected to polymorphism genotyping via the TaqMan qPCR method. Odds ratio (OR) and 95% confidence interval (CI) were used to determine hepatoblastoma susceptibility variants. The rs236170 A > G, rs236188 G > A and rs236110 C > A polymorphisms were significantly associated with hepatoblastoma risk. Combination analysis of the four polymorphisms revealed that children bearing 1-4 risk genotypes were at significantly enhanced hepatoblastoma risk compared to those without risk genotype (adjusted OR = 1.52, 95% CI = 1.19-1.95, p = 0.0008). We also conducted stratification analyses by age, sex and clinical stage. Ultimately, we found that the rs236110 C > A was significantly associated with the downregulation of MCM8, a neighbouring gene of TRMT6. In conclusion, we identified three susceptibility loci in the TRMT6 gene for hepatoblastoma. Our findings warrant further validation by extensive case-control studies across different ethnicities.

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BACKGROUND: N1-methyladenosine (m1A) is a recently identified mRNA modification. However, it is still unclear that how m1A alteration affects the development of colorectal cancer (CRC). AIMS: The landscape of m1A modification patterns regarding tumor immune microenvironment (TIME) in CRC is a lack of knowledge. Thus, this study will utilize the public database to comprehensively evaluate of multiple m1A methylation regulators in CRC. METHODS AND RESULTS: We retrospectively analyzed 398 patients with CRC and 39 healthy people for negative control, using the The Cancer Genome Atlas (TCGA) database to evaluate m1A modification patterns regarding tumor immune microenvironment (TIME) in CRC. The m1Ascore was developed via principal component analysis. And its clinical value in prognosis of CRC was further explored. Our study revealed 12 key m1A-related DEGs including CLDN3, MUC2 and CCDC85B which are identified associated with invasion and metastasis in CRC. The most important biological processes linked to weak immune response and poor prognosis were the regulation of RNA metabolism and RNA biosynthesis. Furthermore, we found that compared to patients with low m1A scores, those with high m1A scores had higher percentage, larger tumor burdens, and worse prognosis. CONCLUSION: Significantly diverse m1A modification patterns can be seen in CRC. Through its impact on TIME and immunological dysfunction, the heterogeneity of m1A alteration patterns influences the prognosis of CRC. This study provided novel insights into the m1A modification in CRC which might promote the development of personalized immunotherapy strategies.

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tRNA methyltransferase 6 (TRMT6)is an enzyme catalyzing N1-methyladenosine, a reversible modification in RNA, including tRNA, mRNA, rRNA, and lncRNA. Increasing evidence has shown the implications of this post-transcriptional modification and its regulators in carcinogenesis. However, its roles in Wilms tumor haven't been reported. In this study, four TRMT6 gene polymorphisms (rs236170 A > G, rs451571 T > C, rs236188 G > A, and rs236110 C > A) were tested for association with susceptibility to Wilms tumor, the most frequently diagnosed pediatric renal tumor. TaqMan method was adopted to analyze the genotypes of these polymorphisms in 414 cases and 1199 controls. Among the four TRMT6 gene polymorphisms, only the rs236110 C > A displayed a significant association with the risk of Wilms tumor [AA vs. CC, adjusted odds ratio (OR) = 1.93, 95 % confidence interval (CI) = 1.14-3.27, P = 0.015]. This association was confirmed under the recessive models (AA vs. CC/CA, OR = 1.92, 95 % CI = 1.14-3.23, P = 0.015). Furthermore, after stratifying by age, gender, and clinical stage, we mainly detected significant associations for the rs236110 C > A in children older than 18 months, boys, and those with stage IV or III + IV diseases. The rs236110 A allele was significantly associated with decreased expression of MCM8. In conclusion, we identified the rs236110 C > A in the TRMT6 gene as a Wilms tumor susceptibility locus, and this polymorphism warrants more validation studies to be translated into individualized risk prediction strategies for children.

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Cerebral ischaemia‒reperfusion injury (IRI), during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated mouse neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RNA binding proteins (RBPs) interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA‒miRNA-mRNA competing endogenous RNA (ceRNA) mechanism and that 3' untranslated region (3'UTR) modification of mRNAs can hinder miRNA-mRNA binding. Three modification patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA modification and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

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Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m1 A RNA modification plays critical role in many biological processes. However, the role of m1 A modification in CRC remains unclear. Here, we find that the m1 A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes CRC metastasis in vitro and in vivo. Mechanistically, knockdown of ALKBH1 results in a decrease in methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) expression, probably due to m1 A modification of METTL3 mRNA, followed by m6 A demethylation of SMAD family member 7 (SMAD7) mRNA. In addition, downregulation of SMAD7 establishes an aggressive phenotype. More importantly, the cell migration and invasion defects caused by ALKBH1 depletion or METTL3 depletion are significantly reversed by SMAD7 silencing. Considering these results collectively, we propose that ALKBH1 promotes CRC metastasis by destabilizing SMAD7 through METTL3.

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RNA methylation plays crucial roles in gene expression and has been indicated to be involved in tumorigenesis, while it is still unclear whether m1A modifications have potential roles in the prognosis of hepatocellular carcinoma (HCC). In this study, we comprehensively analyzed RNA sequencing (RNA-seq) data and clinical information using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We collected 10 m1A regulators and performed consensus clustering to determine m1A modification patterns in HCC. The CIBERSORT method was utilized to evaluate the level of immune cell infiltration. Principal component analysis was used to construct the m1A-score model. In the TCGA-LIHC cohort, the expression of all 10 m1A regulators was higher in tumor tissues than in normal control tissues, and 8 of 10 genes were closely related to the prognosis of HCC patients. Two distinct m1A methylation modification patterns (Clusters C1 and C2) were identified by the 10 regulators and were associated with different overall survival, TNM stage and tumor microenvironment (TME) characteristics. Based on the differentially expressed genes (DEGs) between C1 and C2, we identified three gene clusters (Clusters A, B and C). C1 with a better prognosis was mainly distributed in Cluster C, while Cluster A contained the fewest samples of C1. An m1A-score model was constructed using five m1A regulators related to prognosis. Patients with higher m1A scores showed a poorer prognosis than those with lower scores in the TCGA-LIHC and GSE14520 datasets. In conclusions, our study showed the vital role of m1A modification in the TME and progression of HCC. Quantitative evaluation of the m1A modification patterns of individual patients facilitates the development of more effective biomarkers for predicting the prognosis of patients with HCC.

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Post-transcriptional modifications of tRNA molecules play crucial roles in gene expression and protein biosynthesis. Across the genera, methylation of tRNAs at N1 of adenosine 58 (A58) by AtTRM61/AtTRM6 complex plays a critical role in maintaining the stability of initiator methionyl-tRNA (tRNAiMet). Recently, it was shown that mutation in AtTRM61 or AtTRM6 leads to seed abortion. However, a detailed study about the AtTRM61/AtTRM6 function in plants remains vague. Here, we found that AtTRM61 has a conserved functional structure and possesses conserved binding motifs for cofactor S-adenosyl-L-methionine (AdoMet). Mutations of the complex subunits AtTRM61/AtTRM6 result in embryo and endosperm developmental defects. The endosperm and embryo developmental defects were conditionally complemented by Attrm61-1/ + FIS2pro::AtTRM61 and Attrm61-1/ + ABI3pro::AtTRM61 indicating that AtTRM61 is required for early embryo and endosperm development. Besides, the rescue of the fertility defects in trm61/ + by overexpression of initiator tRNA suggests that AtTRM61 mutation could diminish tRNAiMet stability. Moreover, using yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays, we showed that AtMPK4 physically interacts with AtTRM61. The data presented here suggest that AtTRM61 has a conserved structure and function in Arabidopsis. Also, AtTRM61 may be required for tRNAiMet stability, embryo and endosperm development.

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Background: recently, many researches have concentrated on the relevance between N1-methyladenosine (m1A) methylation modifications and tumor progression and prognosis. However, it remains unknown whether m1A modification has an effect in the prognosis of ovarian cancer (OC) and its immune infiltration. Methods: Based on 10 m1A modulators, we comprehensively assessed m1A modification patterns in 474 OC patients and linked them to TME immune infiltration characteristics. m1Ascore computed with principal component analysis algorithm was applied to quantify m1A modification pattern in OC patients. m1A regulators protein and mRNA expression were respectively obtained by HPA website and RT-PCR in clinical OC and normal samples. Results: We finally identified three different m1A modification patterns. The immune infiltration features of these m1A modification patterns correspond to three tumor immune phenotypes, including immune-desert, immune-inflamed and immune-excluded phenotypes. The results demonstrate individual tumor m1A modification patterns can predict patient survival, stage and grade. The m1Ascore was calculated to quantify individual OC patient's m1A modification pattern. A high m1Ascore is usually accompanied by a better survival advantage and a lower mutational load. Research on m1Ascore in the treatment of OC patients showed that patients with high m1Ascore showed marked therapeutic benefits and clinical outcomes in terms of chemotherapy and immunotherapy. Lastly, we obtained four small molecule drugs that may potentially ameliorate prognosis. Conclusion: This research demonstrates that m1A methylation modification makes an essential function in the prognosis of OC and in shaping the immune microenvironment. Comprehensive evaluation of m1A modifications improves our knowledge of immune infiltration profile and provides a more efficient individualized immunotherapy strategy for OC patients.

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N1-methyladenosine (m1A) modification widely participates in the occurrence and progression of numerous diseases. Nevertheless, the potential roles of m1A in the tumor immune microenvironment (TIME) are still not fully understood. Based on 10 m1A methylation regulators, we comprehensively explored the m1A modification patterns in 502 patients with oral squamous cell carcinoma (OSCC). The m1A modification patterns were correlated with TIME characteristics and the m1A score was established to evaluate the effect of the m1A modification patterns on individual OSCC patients. The TIME characteristics and survival outcomes under the three m1A modification patterns were significantly distinct. OSCC patients in the high m1A score group were characterized by poorer prognosis, lower immune infiltration, lower ssGSEA score, lower expression levels of immune checkpoint molecules, and higher tumor mutation loads. The present study revealed that m1A modification might be associated with the TIME in OSCC, and has potential predictive ability for the prognosis of OSCC.

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