m6A Regulators Research Articles

Relationship between M6A methylation regulator and prognosis in patients with hepatocellular carcinoma after transcatheter arterial chemoembolization

BackgroundPatients with mid-stage HCC (hepatocellular carcinoma) may benefit from transcatheter arterial chemoembolization (TACE). However, patient efficacy varies widely, and the detailed assessment index is unknown. The most general methylation alteration in mRNA (Messenger RNA), N6-methyladenosine (m6A), is controlled by the m6A regulator, which is associated with the emergence of tumors. To include the molecular causes of cancer, competition with ceRNA (endogenous RNA) networks is crucial. However, the exact processes they contribute to TACE HCC remain uncertain. The purpose of this study was tantamount to investigating the possible function of ceRNA networks and m6A regulators in patients with TACE HCC. MethodsGenes Associated with m6A were discovered using the TACE GEO (Gene Expression Omnibus) dataset. An additional estimate of M6A-associated DEGs (differentially expressed genes) was used to create a predictive response model, which is required. LncRNA-miRNA and miRNA-mRNA interactions were then predicted, the regulatory ceRNA network was set up using Cytoscape software, and target genes were identified using GEPIA online analysis. The connection between immunological checkpoints, immune cell marker genes, and target genes for immune cells was also examined. ResultsThe detection of 4 m6A-associated DEGs, the development and evaluation of 2 Machine learning models, and the development of risk models that accurately predicted the response rate of specific patients. Additionally, we obtained two miRNAs (micro RNAs)and six lncRNAs (Long non-coding RNAs), forming an 8-pair ceRNA network, and the target gene LRPPRC deletion of one copy number and gene expression was highly correlated with the amount of Tregs immune cells. LRPPRC was related positively with NRP1, IRF5, and ITGAM and negatively with CCR7 and CD8B among immune cell marker genes. We also discovered that LRPPRC correlates positively with immune checkpoint CD274 cells. ConclusionThe response of HCC patients to TACE therapy may be predicted using a model based on four gene expression data. We also developed a ceRNA network for TACE HCC related to m6A, which offered suggestions for more research into its molecular processes and possible prognostic indicators.

Emerging role of N6-methyladenosine RNA methylation in lung diseases.

In recent years, with the increase of air pollution, smoking, aging, and respiratory infection, the incidence rate and mortality of lung diseases are increasing annually, which has become a major hazard to human health. N6-methyladenosine (m6A) RNA methylation is the most abundant modifications in eukaryotes, and such modified RNA can be specifically recognized and combined by m6A recognition proteins and then mediate RNA splicing, maturation, enucleation, degradation, and translation. More and more studies have revealed that the m6A modification is involved in the pathogenesis and development of some diseases; however, the mechanisms of m6A in lung diseases are poorly understood. In this review, we summarize the latest progress in the biological function of m6A modifications in lung diseases and discuss the potential therapeutic and prognostic strategies. The dysregulation of global m6A levels and m6A regulators may affect the occurrence and development of asthma, chronic obstructive pulmonary disease, lung cancer, and other lung diseases through inflammation and immune function. In lung cancer, this modification has an important impact on malignant cell proliferation, migration, invasion, and drug resistance. In addition, abnormally changed m6A-modified proteins in lung cancer tissue samples and circulating tumor cells (CTCs) may be used as diagnostic and prognostic markers of lung cancer. Models composed of multiple m6A regulators can be used to evaluate the risk prediction or prognosis of asthma and pulmonary fibrosis. In general, the in-depth study of m6A modifications is a frontier direction in disease research. It provides novel insights for understanding of the molecular mechanisms underlying disease occurrence, development, and drug resistance, as well as for the development of effective novel therapeutics.

M6A RNA methylation regulator-related signatures exhibit good prognosis prediction ability for head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) has become the sixth most common malignant disease worldwide and is associated with high mortality, with an overall 5-year survival rate of less than 50%. Recent studies have demonstrated that aberrantly expressed m6A regulators are involved in multiple biological and pathological processes, including cancers, but the specific mechanisms of m6A regulators in HNSCC are not well elucidated. In this study, we adopted The Cancer Genome Atlas (TCGA)-HNSCC database and performed a consensus clustering analysis to classify the HNSCC samples. Least absolute shrinkage and selection operator (LASSO) regression was applied to construct an m6A signature-based HNSCC risk prediction model. Cell type identification based on estimating relative subsets of RNA transcripts (CIBERSORT) algorithms was adopted to evaluate the immune cell infiltration level in the tumor microenvironment. Based on the expression of m6A regulators in HNSCC, we identified two clusters, cluster 1 (C1) and cluster 2 (C2). C2 showed a better prognosis than C1 and was mainly enriched in the HIPPO, MYC, NOTCH, and NRF signaling pathways. We constructed an m6A signature-based risk score model and classified patients into high- and low-risk score subgroups. The high-risk-score group showed poor clinical characteristics, higher immune infiltration levels, higher chemokine and chemokine receptor expression levels, and lower immune checkpoint gene expression than the low-risk-score subgroup. In conclusion, our comprehensive analysis suggests that the m6A signature-based risk score might function as a good prognostic predictor. Our study may provide novel therapeutic clues and help predict the prognosis of HNSCC.

M6A-binding protein IGF2BP1 promotes the malignant phenotypes of lung adenocarcinoma.

BackgroundLung adenocarcinoma (LUAD), the most common type of lung cancer, poses a significant threat to the life of patients. N6-methyladenosine modification is the most abundant epigenetic modification and may play an important role in the lung carcinogenesis. IGF2BP1 is a newly discovered m6A-binding protein, but little is known about its role in LUAD.MethodsData from TCGA, GEO, Kaplan–Meier Plotter, and GEPIA databases were systematically analyzed to access the expression and prognostic value of IGF2BP1 on LUAD. Real-time polymerase chain reaction, Western blot, and immunohistochemistry were performed to detect the mRNA and protein level of IGF2BP1 in LUAD tissues and para-carcinoma tissues. Functional cell experiments, including Cell Counting Kit-8 assay, Transwell invasion assay, wound healing assay, Annexin V-FITC/PI double-staining assay, and TUNEL assay, were used to investigate the functions of IGF2BP1 on LUAD cell proliferation, invasion, migration, and apoptosis, respectively. The top 50 genes that were positively or negatively related to the expression of IGF2BP1 were identified, and pathway enrichment analysis was performed. m6A modification sites within IGF2BP1-related genes were predicted by SRAMP.Result16 m6A regulators were significantly differentially expressed in LUAD tissues. IGF2BP1 was upregulated in LUAD tissues compared with para-carcinoma tissues. High expression of IGF2PB1 was significantly associated with higher clinical stages and poor prognosis of LUAD patients. Furthermore, our functional experiments indicated that IGF2BP1 facilitated cell proliferation, invasion, and migration and suppressed apoptosis in LUAD. Functional enrichment analysis of IGF2BP1-related genes indicated enrichment in several pathways related to oncogenesis. Additionally, m6A modification sites were detected within IGF2BP1-related genes.ConclusionsOur findings demonstrate that IGF2BP1 plays a contributory role in the development and progression of LUAD. IGF2BP1 has the potential to become a prognostic predictor and therapeutic target for LUAD.

Effects of writers, erasers and readers within miRNA-related m6A modification in cancers.

As one of the most abundant post-transcriptional mRNA modifications, N6-methyladenosine (m6A) has attracted extensive attention from scientists. Emerging evidence indicates that m6A modification plays a significant role in cancer-related signalling pathways. Existing research demonstrates that m6A modifications were also identified in miRNAs and contribute to cancer-related signalling pathways. A literature retrieval has been performed to collect m6A-miRNA-related original articles published in recent years. Later, a systematic analysis has been conducted to abstract and classify the relationships between m6A modification and miRNAs, and their contributions to tumorigenesis and cancer development. Accumulating literature provides important insights into multiple relationships between m6A modifications and miRNAs. Mechanically, m6A writer and eraser alter pri-miRNAs m6A levels, and m6A readers could dually modulate pri-miRNAs processing and pri-miRNAs degradation. It is also been demonstrated that miRNAs impair m6A regulators' translation to influence m6A medication function in return. Aberrant expressions of m6A regulators and miRNAs could dysregulate proliferative, apoptosis, cell adhesion-related, and malignant transformation signalling pathways, and contribute to tumour occurrence and development. This review summarizes the interrelationship between m6A modification and miRNAs; highlights the combined effects of each type of m6A regulator and miRNAs in cancers. These findings enhance our understanding of m6A-miRNAs' multiple interactions and significant modulatory role in tumorigenesis and progression.

Prognostic N6-methyladenosine (m6A)-related lncRNA patterns to aid therapy in pancreatic ductal adenocarcinoma

Background: Mounting research studies have suggested the indispensable roles of N6-methyladenosine (m6A) RNA modification in carcinogenesis. Nevertheless, it was little known about the potential function of m6A-related lncRNAs in sample clustering, underlying mechanism, and anticancer immunity of pancreatic ductal adenocarcinoma (PDAC). Methods: PDAC sample data were obtained from TCGA-PAAD project, and a total of 23 m6A regulators were employed based on published articles. Pearson correlation and univariate Cox regression were analyzed to determine m6A-related lncRNAs with prognostic significance to identify distinct m6A-related lncRNA subtypes by consensus clustering. Next, the least absolute shrinkage and selection operator (LASSO) algorithm was applied for constructing an m6A-related lncRNA scoring system, further quantifying the m6A-related lncRNA patterns in individual samples. Gene set variation analysis (GSVA) was employed to assign pathway activity estimates to individual samples. To decode the comprehensive landscape of TME, the CIBERSORT method and ESTIMATE algorithm were analyzed. The half-maximal inhibitory concentration (IC50) of chemotherapeutic agents was predicted with the R package pRRophetic. Finally, a quantitative real-time polymerase chain reaction was used to determine TRPC7-AS1 mRNA expression in PDAC. Results: Two distinct m6A-related lncRNA patterns with different clinical outcomes, TEM features, and biological enrichment were identified based on 45 prognostic m6A-related lncRNAs. The identification of m6A-related lncRNA patterns within individual samples based on risk scores contributed to revealing biological signatures, clinical outcomes, TEM characterization, and chemotherapeutic effects. A prognostic risk-clinical nomogram was constructed and confirmed to estimate m6A-related lncRNA patterns in individual samples. Finally, the biological roles of TRPC7-AS1 were revealed in PDAC. Conclusion: This work comprehensively elucidated that m6A-related lncRNA patterns served as an indispensable player in prognostic prediction and TEM features. Quantitative identification of m6A-related lncRNA patterns in individual tumors will contribute to sample stratification for further optimizing therapeutic strategies.

The emerging therapeutic target of dynamic and reversible N6-methyladenosine modification during cancer development.

As a reversible and dynamic epigenetic modification, N6-methyladenosine (m6A) modification is ubiquitous in eukaryotic cells. m6A methylation is prevalent in almost all RNA metabolism processes that affect the fate of cells, including cancer development. As indicated by the available evidence, targeting m6A regulators may play a crucial role in tumor therapy and multidrug resistance. Currently, many questions remain uncovered. Here, we review recent studies on m6A modification in various aspects of tumor progression, tumor immunity, multidrug resistance, and therapeutic targets to provide new insight into the m6A methylation process.

Characterization of m6A methylation modifications and tumor microenvironment infiltration in thyroid cancer.

Thyroid cancer (TC) is the most common endocrine malignancy worldwide, and immunotherapy is a new cancer treatment that stimulates and enhances the natural ability of the immune system to fight cancer cells. The role of RNA N6-methyladenosine (m6A) related genes in these challenges has recently become a research hotspot, but he potential role of m6A modifications in tumor microenvironment (TME) cell infiltration remains unknown. There is growing evidence that m6A plays a critical role in the regulation of gene expression by participating in important biological processes. A comprehensive analysis of the m6A regulator-mediated infiltration characteristics of the TME will help advance the understanding of immune regulation in thyroid tumors. This study assessed m6A modification modes in 510 thyroid cancer samples from the Cancer Genome Atlas (TCGA) databases according to a comprehensive set of 24 m6A regulators. In this study, we analyzed the biological characteristics and m6A methylation modification patterns. Based on this, we constructed m6A signatures and analyzed m6A modification features in tumor somatic mutations and TCGA molecular subtypes. These modification modes were systematically linked to TME cell infiltration signatures. m6A modification patterns were comprehensively assessed and correlated with immune cell infiltration features in the TME. An unsupervised clustering approach was applied and three distinct m6A modification subtypes and three m6A-associated gene subtypes were identified. Additionally, three distinct m6A methylation modification modes were identified in the thyroid cancer samples. The TME profiles of the identified genetic subtypes were strongly congruent with the immuno-heat and immuno-cold phenotypes. The results revealed that m6A modifications play an integral role in the diversity and complexity of thyroid carcinomas. Evaluating the m6A modification patterns of individual tumors will create more efficient immunotherapeutic strategies. A comprehensive analysis of the role of TME in thyroid cancer provides a research idea for studying the effect of m6A epigenetics on thyroid tumors and their immune microenvironment.

Integrative Analysis of N6-Methyladenosine-Related Enhancer RNAs Identifies Distinct Prognosis and Tumor Immune Micro-Environment Patterns in Head and Neck Squamous Cell Carcinoma.

Simple SummaryHead and neck squamous cell carcinoma (HNSCC) has high morbidity and mortality. The interaction between immune cells and tumor cells in the tumor micro-environment is an important factor affecting the tumor progression and prognosis of HNSCC patients. More biomarkers and targets need to be explored to improve patient outcomes. The m6A modification on enhancer RNAs (eRNAs) is associated with the signature of active enhancer, and the function of m6A driving eRNAs in tumor progression has not been reported. In this study, we screened and identified a risk model containing 5 m6A-related eRNA, which can better predict the survival and immunotherapy outcome of patients. The role of m6A-related eRNA in HNSCC cells was verified in vitro. We also combined the risk score and multiple clinical features to construct a nomogram for predicting OS of HNSCC patients, which provides an effective quantitative analysis tool for guiding the personalized precise treatment for patients.At present, the prognostic value of N6-methyladenosine (m6A)-related enhancer RNAs (eRNAs) for head and neck squamous cell carcinoma (HNSCC) still remains unclear. Our study aims to explore the prognostic value of m6A-related eRNAs in HNSCC patients and their potential significance in immune infiltration and immunotherapy. We constructed a 5 m6A-related eRNAs risk model from The Cancer Genome Atlas (TCGA) HNSCC dataset, using univariate and multivariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis. Based on the SRAMP website and in vitro experiments, it was verified that these 5 m6A-related eRNAs had m6A sites, the expression of which was regulated by corresponding m6A regulators. Moreover, we constructed a nomogram base on 5 m6A-related eRNAs and confirmed the consistency and robustness of an internal TCGA testing set. Further analysis found that the risk score was positively associated with low overall survival (OS), tumor cell metastasis, metabolic reprogramming, low immune surveillance, lower expression of immune-related genes, and higher expression of targeted genes. Finally, we verified that silencing MIR4435-2HG inhibited HNSCC cell migration and invasion. This study contributes to the understanding of the characteristics of m6A-related eRNAs in HNSCC and provides a reference for effective immunotherapy and targeted therapy.

Integrated Analyses of m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Pan-Cancer.

The invasion of immune cells in the tumor microenvironment (TME) is closely related to cancer development. Studies have demonstrated that N6-methyladenosine (m6A) can affect the invasion of immune cells in TME as well as cancer development. We comprehensively analyzed the RNA-seq data of 16 different cancer types based on 20 m6A regulators and identified two distinct m6A modification patterns, which were closely associated with TME cell infiltration and overall patient survival. Then, we used principal component analysis (PCA) to construct m6Ascore based on the expression of m6A-related prognostic genes, which can successfully predict patient survival. The low-m6Ascore subtype is characterized by more immune cell infiltration, good prognosis and lower TNM stages, while the high-m6Ascore subtype is characterized by low immune infiltration, stromal activation, and poor prognosis. m6Ascore was also closely associated with immunotherapy response and was significantly higher in complete response/partial response (CR/PR) patients than in stable disease/progressive disease (SD/PD) patients in both immunotherapy cohorts. Therefore, our study indicates that m6A modification plays an important role in the prognosis of pan-cancer and the formation of complex TME in pan-cancer. Our research helps to improve the cognition of m6A modifications at pan-cancer levels and identify more effective strategies for immunotherapy.

LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The main methods of treating pancreatic cancer are surgery and chemotherapy, but the treatment efficacy is low with a poor prognosis. Immunotherapy represented by PD-1/PD-L1 has brought a milestone progress in the treatment of pancreatic cancer. However, the unique tumor microenvironment of pancreatic cancer presents challenges for immunotherapy. In addition, m6A is a common RNA modification and a potential molecular target in tumor therapy. The expression pattern of m6A in pancreatic cancer is still unclear. LncRNAs also play an essential role in pancreatic cancer development and treatment. In this study, we found that some m6A regulators were significantly elevated in pancreatic cancer and associated with the expression of PD-1/PD-L1. Moreover, we observed that METTL3 can increase the expression of PD-L1. Notably, METTL3 positively regulates the expression of lncRNA MALAT1 in pancreatic cancer cells. Strikingly, lncRNA MALAT1 increased the expression of PD-L1 in pancreatic cancer cells. This finding indicated that METTL3 regulated the expression of PD-L1 possibly via targeting lncRNA MALAT1 in pancreatic cancer cells. Lastly, MALAT1 governed the viability of pancreatic cancer cells. Taken together, lncRNA MALAT1 is involved in METTL3-mediated promotion of PD-L1 expression in pancreatic cancer.

Role of m6A RNA methylation in the development of hepatitis B virus-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver malignancy that can be developed from hepatitis B and cirrhosis. Many pathophysiological alterations, including hepatitis B virus (HBV) DNA integration, oxidative stress, cytokine release, telomerase homeostasis, mitochondrial damage, epigenetic modification, and tumor microenvironment, are involved in the biological process from hepatitis B to cirrhosis and HCC. N6-methyladenosine (m6A), as an epitranscriptomic modification of RNAs, can regulate the stability, splicing, degradation, transcription, and translation of downstream target RNAs in HBV and liver cancer cells. m6A regulators (writers, erasers, and readers) play an important role in the pathogenesis of HBV-associated HCC by regulating cell proliferation, apoptosis, migration, autophagy, differentiation, inflammation, angiogenesis, and tumor microenvironment. This review summarizes the current progress of m6A methylation in the molecular mechanisms, biological functions, and potential clinical implications of HBV-associated HCC.

Integrated Analyses of m6A Regulator-Based Signature on Its Clinical Application and Immunogenomic Landscape in Stomach Adenocarcinoma.

Background The whole tumor microenvironment (TME) infiltration features monitored by integrated roles of different RNA N6-methyladenosine (m6A) regulators remain elusive. Our study is aimed at exploring the association between m6A modification patterns, TME cell-infiltrating levels, and patients' prognosis in stomach adenocarcinoma (STAD) patients. Methods Consensus clustering was performed based on the integrated analyses of 17 m6A regulators and 229 m6A-related hallmark genes in STAD (The Cancer Genome Atlas (TCGA) cohort, n = 443; Gene Expression Omnibus (GEO) GSE57303, n = 70, GSE62254 n = 300, and GSE84437 n = 433). A m6ASig scoring system was calculated by the principal component analysis (PCA), and its prognostic value was validated in an independent dataset GES15459. Results Three m6A clusters were identified among 1246 STAD patients, which had significant overall survival (OS) differences and demonstrated different TME immune cell infiltration and biological behaviors. According to the m6ASig score, which was generated from the m6A-related hallmark genes, STAD patients were divided into the high-m6ASig group (n = 585) and low-m6ASig group (n = 586). Patients in the high-m6ASig group had a notably prolonged OS and higher immune cell infiltration. Moreover, patients with higher m6ASig score were associated with higher microsatellite instability (MSI); higher PD-L1, CTLA4, and ERBB2 expressions; and greater tumor mutation burden (TMB). Patients with higher m6ASig score demonstrated a better immune response and drug sensitivity. Conclusion Our m6ASig scoring system could characterize TME immune cell infiltration, thus predict patient's prognosis and immunotherapy and chemotherapy efficacy, offering a novel tool for the individualized therapeutic implications for STAD patients.

Alterations of m6A RNA methylation regulators contribute to autophagy and immune infiltration in primary Sjögren's syndrome.

N6-methyladenosine (m6A) RNA modification is a new epigenetic regulation mechanism on eukaryotic mRNA. Few autoimmune diseases focused on the role of m6A in their pathogenies, and m6A modulation in the pathological process of primary Sjögren’s syndrome (pSS) is still unknown. In this work, three microarray datasets of pSS patients were downloaded from the GEO database: datasets #1 and #2 from the whole peripheral blood (PB) samples, dataset #3 from the labial salivary gland tissue samples, as well as a PB cohort collected from our hospital. Six differentially expressed m6A regulators were identified by comparing the PB dataset #1 of pSS and healthy controls using the Wilcox test and logistic regression analysis. Among them, four (ALKBH5, RBMX, RBM15B, and YTHDF1) were confirmed as down-regulated in PB dataset #2 and in our PB cohort by RT-PCR, and four (ALKBH5, METTL3, RBM15B, and YTHDF1) were confirmed as down-regulated in the dataset #3 of the labial gland tissue. In addition, discrepantly expressed m6A regulators accompanied by diverse immunocytes, including dendritic cells (DCs), T cells, and CD56dim natural killer cells, and among the regulators, ALKBH5 and METTL3 were comprehensively linked with the infiltrated immune cells. Notably, the most enriched autophagy mechanism mediated by m6A was observed in pSS using functional annotation analysis. Ten hub genes were identified using a protein-protein interaction network, and their expression in PB dataset #2 and the expression of three genes (PIK3CA, STAT1, and MAPK3) in the labial gland tissue dataset #3 were confirmed. Our study provides evidence that m6A methylation is widely involved in the immune infiltration and autophagy of pSS, thus contributing to the pathogenesis of this disease and potentially representing a novel therapeutic target.

Analysis of N6-Methyladenosine RNA Methylation Regulators in Diagnosis and Distinct Molecular Subtypes of Ankylosing Spondylitis.

The most frequent internal modification in eukaryotic mRNA is N6-methyladenosine (m6A). However, what we know about the m6A regulators in Ankylosing spondylitis (AS) is still limited. In our study, eight distinct m6A regulators were selected utilizing Differentially Expressed Gene (DEG) analysis of the Gene Expression Omnibus GSE73754 dataset for making comparisons between AS (Ankylosing spondylitis) and non-AS patients. The random forest model and the nomogram model were used to screen the eight candidate m6A regulators and evaluate their prediction accuracy for the occurrence of AS. Furthermore, based on the selected m6A regulators, the AS patients were divided into two subgroups, and we applied principal component analysis algorithms to calculate their m6A score and evaluate the m6A patterns. Our findings revealed that patients in cluster A were linked to activated CD4 T cell immunity and activated CD8 T cell immunity. With its major contributions in the area of immunology, our research in m6A patterns may benefit the future diagnosis and treatment strategies of AS.

Prognostic value of m6A regulators and the nomogram construction in glioma patients.

Although N6-methyladenosine (m6A) has been implicated in various biological functions in human cancers, its role in predicting the prognosis of glioma remains unclear. In this study, the transcriptome expression profiles and the clinical data of 961 patients were derived from the Chinese Glioma Genome Atlas (CGGA). We comprehensively evaluated the association between the expression of m6A regulators and the prognosis of glioma and established a 3-gene (YTHDF2, FTO, and ALKBH5) risk signature using least absolute shrinkage and selection operator (LASSO) analysis. Patients with a high-risk signature had significantly adverse prognoses. Gene set enrichment analysis (GSEA) analysis revealed that the G2M checkpoint, MTORC1 signaling, epithelial mesenchymal transition, and PI3K-AKT-mTOR signaling were significantly enriched in the high-risk group. Univariate and multivariate Cox regression analyses confirmed the independent prognostic value of this risk signature. We then constructed a nomogram for individualized prediction of overall survival (OS) by integrating clinicopathological features (age, World Health Organization [WHO] grade), treatment information (radiotherapy, temozolomide therapy), and m6A risk signature. The calibration curves showed excellent agreement between the predicted and actual probabilities for the 1-, 3-, and 5-year OS, with a C-index of 0.780 in the training cohort and 0.717 in the validation cohort. Altogether, our study elucidated the important role of m6A regulators in glioma prognosis, which is valuable for the selection of therapeutic methods and clinical management of patients with glioma.

Novel Roles of RNA m6A Methylation Regulators in the Occurrence of Alzheimer's Disease and the Subtype Classification.

Alzheimer’s disease (AD) is one of the most common forms of dementia, closely related to epigenetic factors. N6-methyladenosine (m6A) is the most abundant RNA modification, affecting the pathogenesis and development of neurodegenerative diseases. This study was the first exploration of the combined role of 25 common m6A RNA methylation regulators in AD through the integrated bioinformatics approaches. The 14 m6A regulators related to AD were selected by analyzing differences between AD patients and normal controls. Based on the selected m6A regulators, AD patients could be well classified into two m6A models using consensus clustering. The two clusters of patients had different immune profiles, and m6A regulators were associated with the components of immune cells. Additionally, there were 19 key AD genes obtained by screening differential genes through weighted gene co-expression network and least absolute shrinkage and selection operator regression analysis, which were highly associated with important m6A regulators during the occurrence of AD. More interestingly, NOTCH2 and NME1 could be potential targets for m6A regulation of AD. Taken together, these findings indicate that dysregulation of m6A methylation affects the occurrence of AD and is vital for the subtype classification and immune infiltration of AD.

The Critical Role of RNA m6A Methylation in Gliomas: Targeting the Hallmarks of Cancer.

Gliomas are the most common central cancer with high aggressive-capacity and poor prognosis, remaining to be the threat of most patients. With the blood-brain barrier and highly malignant progression, the efficacy of high-intensity treatment is limited. The N6-methyladenine (m6A) modification is found in rRNA, snRNA, miRNA, lncRNA, and mRNA, influencing the metabolism and translation of these RNAs and consequently regulating the proliferation, metastasis, apoptosis, etc. of glioma cells. The key role that m6A modification in gliomas has played makes it a prospective target for diagnosis and treatment. However, with studying deeper in m6A modification and gliomas, the conclusion and mechanism are abundant and complex. This review focused on the dysregulation of m6A regulators and m6A modification of key genes and pathways in Hallmarks of gliomas. Furthermore, the potential of exploiting m6A modification for gliomas diagnosis and therapeutics was also discussed. This review will summarize the recent studies about m6A modification, revealing that m6A modification plays an important role in the malignant progression, angiogenesis, microenvironment, and genome instability in gliomas by exploring the interaction and network between m6A modification-related regulators and classical tumor-related genes. And it might provide some clue for the molecular mechanism, diagnosis, and treatment of gliomas.

Comprehensive analysis of the expression of N6-methyladenosine RNA methylation regulators in pulmonary artery hypertension.

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling. The development of PAH involves N6-methyladenosine (m6A) modification. However, the functional role of m6A regulators in PAH and the underlying regulatory mechanisms remain unknown so far. Methods: Microarray data (GSE149713) for monocrotaline induced PAH (MCT-PAH) rat models were downloaded and screened for differentially expressed genes (DEGs) and m6A regulators. Next, we screened for differentially expressed m6A regulators in endothelial cells (ECs), smooth muscle cells (SMCs), fibroblasts, interstitial macrophages, NK cells, B cells, T cells, regulatory T cells (Tregs) using scRNA sequencing data. The target DEGs of m6A regulators in ECs, SMCs, fibroblasts, and Tregs were functionally annotated using the Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In addition, the cellular interaction analysis was performed to reveal the receptor—ligand pairs regulated by m6A regulators. Pseudo-time trajectory analyses were performed and a ceRNA network of lncRNAs-miRNAs-mRNAs was constructed in SMCs. Furthermore, the RNA transcriptome sequencing data for the SMCs isolated from idiopathic PAH (IPAH) patients (GSE144274) were validated for differentially expressed m6A regulators. Moreover, the HNRNPA2B1 levels in the lung samples from PAH patients and MCT-PAH were determined using immunohistochemistry. Results: The m6A regulators were observed to be dysregulated in PAH. HNRNPA2B1expression level was increased in the PASMCs of scRNAs and IPAH patients. The target DEGs of HNRNPA2B1 were enriched in the regulation of muscle cell differentiation and vasculature development in PASMCs. The HNRNPA2B1 expression levels determined were consistent with the proliferation-related and collagen synthesis-related gene COL4A1. Moreover, the predicted transcription factors (TFs) foxd2/3 and NFκB could be involved in the regulation of HNRNPA2B1. HNRNPA2B1 might be regulating SMCs proliferation and phenotypic transition via rno-miR-330–3p/TGFβR3 and rno-miR-125a-3p/slc39a1. In addition, HNRNPA2B1 was observed to be highly expressed in the lung samples from MCT-PAH rat models and patients with PAH. Conclusion: In summary, the present study identified certain key functional m6A regulators that are involved in pulmonary vascular remodeling. The investigation of m6A patterns might be promising and provide biomarkers for diagnosis and treatment of PAH in the future.

METTL16 predicts a favorable outcome and primes antitumor immunity in pancreatic ductal adenocarcinoma.

Pancreatic carcinogenesis is a complicated and multi-step process. It is substantially assisted by N6-methyladenosine (m6A) RNA modification, especially when mutations of driver genes (KRAS, TP53, CDKN2A, and SMAD4) occur. However, the underlying mechanism remains obscure. In this research, we identified m6A regulators as potential biomarkers when mutations of driver genes occur, and investigated the role of these m6A candidates in pancreatic ductal adenocarcinoma (PDA). We first estimated the abnormal expression patterns of potential m6A regulators when all the driver genes are mutated, using The Cancer Genome Atlas and Gene Expression Omnibus databases. METTL16, an m6A“writer,” was chosen as a unique candidate of PDA, owing to its markedly differential expression under mutations of all driver genes (KRAS, TP53, CDKN2A, and SMAD4) and its favorable prognostic value. Moreover, METTL16 was under-expressed in PDA tissues and cell lines. Consistently, gain- and loss-of-function experiments indicated that it had a tumor suppressor role in vitro and in vivo. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that METTL16 may have an effect on the tumor microenvironment. Notably, a markedly positive association between METTL16 expression and infiltration of B cells and CD8+ T cells was observed according to the CIBERSORT and TIMER databases. Enhanced expression of immune checkpoints and cytokines was elicited in patients with over-expression of METTL16. Notably, decreased expression of PD-L1 was observed when upregulation of METTL16 expression occurred in MIA PaCa-2 cells, while increased expression of PD-L1 existed when downregulation of METTL16 happened in HPAF-II cells. Collectively, these findings highlight the prognostic value of METTL16, and indicate that it is a potential immunotherapy target that could be used to regulate the tumor microenvironment and promote antitumor immunity in PDA.