scholarly journals N6-Methyladenosine RNA modification in cerebrospinal fluid as a novel potential diagnostic biomarker for progressive multiple sclerosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Fei Ye ◽  
Tianzhu Wang ◽  
Xiaoxin Wu ◽  
Jie Liang ◽  
Jiaoxing Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Clustering Analysis ◽  
Roc Curves ◽  
Progressive Multiple Sclerosis ◽  
Rna Modification ◽  
Diagnostic Model ◽  
Consensus Clustering ◽  
Rna Methylation ◽  
M6a Rna Methylation

Abstract Background Progressive multiple sclerosis (PMS) is an uncommon and severe subtype of MS that worsens gradually and leads to irreversible disabilities in young adults. Currently, there are no applicable or reliable biomarkers to distinguish PMS from relapsing–remitting multiple sclerosis (RRMS). Previous studies have demonstrated that dysfunction of N6-methyladenosine (m6A) RNA modification is relevant to many neurological disorders. Thus, the aim of this study was to explore the diagnostic biomarkers for PMS based on m6A regulatory genes in the cerebrospinal fluid (CSF). Methods Gene expression matrices were downloaded from the ArrayExpress database. Then, we identified differentially expressed m6A regulatory genes between MS and non-MS patients. MS clusters were identified by consensus clustering analysis. Next, we analyzed the correlation between clusters and clinical characteristics. The random forest (RF) algorithm was applied to select key m6A-related genes. The support vector machine (SVM) was then used to construct a diagnostic gene signature. Receiver operating characteristic (ROC) curves were plotted to evaluate the accuracy of the diagnostic model. In addition, CSF samples from MS and non-MS patients were collected and used for external validation, as evaluated by an m6A RNA Methylation Quantification Kit and by real-time quantitative polymerase chain reaction. Results The 13 central m6A RNA methylation regulators were all upregulated in MS patients when compared with non-MS patients. Consensus clustering analysis identified two clusters, both of which were significantly associated with MS subtypes. Next, we divided 61 MS patients into a training set (n = 41) and a test set (n = 20). The RF algorithm identified eight feature genes, and the SVM method was successfully applied to construct a diagnostic model. ROC curves revealed good performance. Finally, the analysis of 11 CSF samples demonstrated that RRMS samples exhibited significantly higher levels of m6A RNA methylation and higher gene expression levels of m6A-related genes than PMS samples. Conclusions The dynamic modification of m6A RNA methylation is involved in the progression of MS and could potentially represent a novel CSF biomarker for diagnosing MS and distinguishing PMS from RRMS in the early stages of the disease.

scholarly journals The Prognostic Values of m6A RNA Methylation Regulators in Thyroid Carcinoma

2020 ◽  
Author(s):  
Di Zhang ◽  
Yue Ma ◽  
Xu-Chen Cao ◽  
Li Fu ◽  
Yue Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Ontology ◽  
Thyroid Carcinoma ◽  
Signaling Pathways ◽  
Rna Modification ◽  
Consensus Clustering ◽  
Gene Set Enrichment ◽  
Rna Methylation ◽  
Gene Set ◽  
M6a Rna Methylation

Abstract Background: N6-methyladenosine (m6A) is the most common RNA modification and regulates RNA splicing, translation, translocation, and stability. Aberrant expression of m6A has been reported in various types of human cancers. m6A RNA modification is dynamically and reversibly mediated by different regulators, including methyltransferase, demethylases, and m6A binding proteins. However, the role of m6A RNA methylation regulators in thyroid cancer remains unknown. The aim of this study is to investigate the effect of the 13 main m6A RNA modification regulators in thyroid carcinoma.Methods: The gene expression profile of m6A RNA modification regulations and clinical information of patients with thyroid carcinoma were obtained from The Cancer Genome Atlas database. Consensus clustering was applied to identify two clusters of thyroid carcinomas with different clinical outcome. LASSO Cox regression analysis was used to construct gene-based prognostic signature based on the expression of m6A RNA methylation regulators. Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and gene set enrichment analyses were performed to explore differential cellular processes and signaling pathways between the two groups based on risk signature.Results: We found that most of the m6A RNA modification regulators are down-regulated in 450 patients with thyroid carcinoma. We identified two clusters based on the gene expression profiles of 13 m6A RNA modification regulators using consensus clustering. The cluster 2 subgroup correlates with an unfavorable outcome compared with the cluster 1 subgroup. In addition, we derived a three m6A RNA modification regulator genes-based risk signature (FTO, RBM15 and KIAA1429), that is an independent prognostic biomarker in patients with thyroid carcinoma. There were significantly different signaling pathways between high and low risk group by Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and gene set enrichment analyses. Moreover, we found that this risk signature could better predict outcome in male than female. Conclusion: Our study revealed the prognostic value of m6A RNA methylation regulators in patients with thyroid carcinoma.

scholarly journals Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival

2021 ◽  
Vol 22 (3) ◽  
pp. 1474
Author(s):  
Yong Li ◽  
Dandan Qi ◽  
Baoli Zhu ◽  
Xin Ye
Keyword(s):  
Hepatocellular Carcinoma ◽  
Protein Kinase ◽  
Clustering Analysis ◽  
Prognostic Model ◽  
Consensus Clustering ◽  
Rna Methylation ◽  
Protein Protein Interaction ◽  
M6a Rna Methylation ◽  
Liver Hepatocellular Carcinoma ◽  
One Way Anova

N6-methyladenosine (m6A) modification on RNA plays an important role in tumorigenesis and metastasis, which could change gene expression and even function at multiple levels such as RNA splicing, stability, translocation, and translation. In this study, we aim to conduct a comprehensive analysis on m6A RNA methylation-related genes, including m6A RNA methylation regulators and m6A RNA methylation-modified genes, in liver hepatocellular carcinoma, and their relationship with survival and clinical features. Data, which consist of the expression of widely reported m6A RNA methylation-related genes in liver hepatocellular carcinoma from The Cancer Genome Atlas (TCGA), were analyzed by one-way ANOVA, Univariate Cox regression, a protein–protein interaction network, gene enrichment analysis, feature screening, a risk prognostic model, correlation analysis, and consensus clustering analysis. In total, 405 of the m6A RNA methylation-related genes were found based on one-way ANOVA. Among them, DNA topoisomerase 2-alpha (TOP2A), exodeoxyribonuclease 1 (EXO1), ser-ine/threonine-protein kinase Nek2 (NEK2), baculoviral IAP repeat-containing protein 5 (BIRC5), hyaluronan mediated motility receptor (HMMR), structural maintenance of chromosomes protein 4 (SMC4), bloom syndrome protein (BLM), ca-sein kinase I isoform epsilon (CSNK1E), cytoskeleton-associated protein 5 (CKAP5), and inner centromere protein (INCENP), which were m6A RNA methylation-modified genes, were recognized as the hub genes based on the protein–protein interaction analysis. The risk prognostic model showed that gender, AJCC stage, grade, T, and N were significantly different between the subgroup with the high and low risk groups. The AUC, the evaluation parameter of the prediction model which was built by RandomForest, was 0.7. Furthermore, two subgroups were divided by consensus clustering analysis, in which stage, grade, and T differed. We identified the important genes expressed significantly among two clusters, including uridine-cytidine kinase 2 (UCK2), filensin (BFSP1), tubulin-specific chaperone D (TBCD), histone-lysine N-methyltransferase PRDM16 (PRDM16), phosphorylase b ki-nase regulatory subunit alpha (PHKA2), serine/threonine-protein kinase BRSK2 (BRSK2), Arf-GAP with coiled-coil (ACAP3), general transcription factor 3C polypep-tide 2 (GTF3C2), and guanine nucleotide exchange factor MSS4 (RABIF). In our study, the m6A RNA methylation-related genes in liver hepatocellular carcinoma were analyzed systematically, including the expression, interaction, function, and prognostic values, which provided an important theoretical basis for m6A RNA methylation in liver cancer. The nine important m6A-related genes could be prognostic markers in the survival time of patients.

scholarly journals Identification of a m6A RNA methylation regulators-based signature for predicting the prognosis of esophageal adenocarcinoma

2020 ◽  
Author(s):  
Yue Zhou ◽  
Shuyan Li ◽  
Liqing Zou ◽  
Tiantian Guo ◽  
Xi Yang ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Clustering Analysis ◽  
Cox Regression ◽  
Area Under The Curve ◽  
Clinical Information ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Cox Regression Analysis ◽  
Rna Methylation ◽  
M6a Rna Methylation

Abstract BackgroundN6-methyladenosine (m6A) is an abundant modification in RNAs that affects RNA metabolism, and it is reported to be closely related to cancer occurrence and metastasis. The aim of this study was to identify novel prognostic biomarkers by using m6A RNA methylation regulators capable of improving the risk-stratification criteria of survival for esophageal adenocarcinoma patients.MethodsThe gene expression data of 16 m6A methylation regulators and its relevant clinical information were extracted from The Cancer Genome Atlas (TCGA) database. The expression pattern of these m6A methylation regulators was evaluated. Consensus clustering analysis was conducted to identify clusters of esophageal adenocarcinoma patients with different prognosis. Univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis were performed to construct multiple-gene risk signature. A survival analysis was carried out to determine the prognosis significance.ResultsTen m6A methylation regulators (HNRNPA2B1, HNRNPC, YTHDF1, METTL3, YTHDF2, RBM15, YTHDC1, WTAP, KIAA1429 and YTHDF3) showed significant up-regulation in tumor tissue. Consensus clustering analysis identified three clusters of esophageal adenocarcinoma patients with different overall survival. A five-gene signature, HNRNPA2B1, KIAA1429, WTAP, METTL16 and ALKBH5, was constructed to serve as a prognostic indicator for distinguish esophageal adenocarcinoma patients with different prognosis. The receiver operator characteristic (ROC) curve which indicated the area under the curve (AUC) were 0.803, demonstrated that the prognostic signature had preferable prediction efficiency.Conclusionsm6A methylation regulators exert as potential biomarkers for prognostic stratification of esophageal adenocarcinoma patients and might help clinicians make individualized therapy for this patient population.

scholarly journals The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Mohammad Burhan Uddin ◽  
Zhishan Wang ◽  
Chengfeng Yang
Keyword(s):  
Signaling Pathways ◽  
Malignant Transformation ◽  
Noncoding Rna ◽  
Rna Modification ◽  
Oncogenic Signaling ◽  
Aberrant Expression ◽  
Rna Methylation ◽  
Rna Molecules ◽  
M6a Rna Methylation ◽  
Oncogenic Signaling Pathways

AbstractThe m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes. Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer. Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms. Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity. In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts. m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations. In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies. The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer.

scholarly journals Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuechai Chen ◽  
Jianan Wang ◽  
Muhammad Tahir ◽  
Fangfang Zhang ◽  
Yuanyuan Ran ◽  
...  
Keyword(s):  
Intervertebral Disc Degeneration ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Degradation Process ◽  
Human Diseases ◽  
Rna Modification ◽  
Rna Methylation ◽  
M6a Rna Methylation ◽  
The Impact

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

scholarly journals The role of m6A modification in the biological functions and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiulin Jiang ◽  
Baiyang Liu ◽  
Zhi Nie ◽  
Lincan Duan ◽  
Qiuxia Xiong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Methylation ◽  
Downstream Target ◽  
Different Types ◽  
M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

scholarly journals The Role of m6A Ribonucleic Acid Modification in the Occurrence of Atherosclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Fu ◽  
Xinghui Cui ◽  
Xiaoyun Zhang ◽  
Min Cheng ◽  
Xiaoxia Li ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Biological Activities ◽  
Rna Modification ◽  
Acid Modification ◽  
Rna Methylation ◽  
Mrna Metabolism ◽  
Modification Process ◽  
M6a Rna Methylation ◽  
The Relationship

The N6-methyladenosine (m6A) modification is the most abundant epitranscriptomic modification in eukaryotic messenger RNA (mRNA). The m6A modification process is jointly regulated by various enzymes and proteins, such as methyltransferases, demethylases and related m6A-binding proteins. The process is dynamic and reversible, and it plays an essential role in mRNA metabolism and various biological activities. Recently, an increasing number of researchers have confirmed that the onset and development of many diseases are closely associated with the molecular biological mechanism of m6A RNA methylation. This study focuses on the relationship between m6A RNA modification and atherosclerosis (AS). It thoroughly summarizes the mechanisms and processes of m6A RNA modification in AS-related cells and the relationships between m6A RNA modification and AS risk factors, and it provides a reference for exploring new targets for the early diagnosis and treatment of AS.

The effect of m6A RNA methylation regulators on tumor microenvironment in clear cell renal cell carcinoma

2021 ◽  
Author(s):  
Shuaishuai Huang ◽  
Xiaodong Qing ◽  
Qiuzi Lin ◽  
Qiaoling Wu ◽  
Xue Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Signature ◽  
Consensus Clustering ◽  
Cell Renal Cell Carcinoma ◽  
Rna Methylation ◽  
M6a Rna Methylation

Abstract Background: m6A RNA methylation and tumor microenvironment (TME) have been reported to play important roles in the progression and prognosis of clear cell renal cell carcinoma (ccRCC). However, whether m6A RNA methylation regulators affect TME in ccRCC remains unknown. Thus, the current study is designed to comprehensively evaluate the effect of m6A RNA methylation regulators on TME in ccRCC.Methods: Transcriptome data of ccRCC was obtained from The Cancer Genome Atlas (TCGA) database. Consensus clustering analysis was conducted based on the expressions of m6A RNA methylation regulators. Survival differences were evaluated by Kaplan-Meier (K-M) analysis between the clusters. DESeq2 package was used to analyze the differentially expressed genes (DEGs) between the clusters. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were analyzed by ClusterProfiler R package. Immune, stromal and ESTIMATE scores were assessed by ESTIMATE algorithm. CIBERSORT algorithm was applied to evaluate immune infiltration. The expressions of human leukocyte antigen (HLA), immune checkpoint molecules, and Th1/IFNγ gene signature associated with TME were also compared between the clusters. TIDE algorithm and subclass mapping were used to analyze the clinical response of different clusters to PD-1 and CTLA-4 blockade. Results: The expressions of fifteen m6A regulators were significantly different between ccRCC and normal kidney tissues. Based on the expressions of those fifteen m6A regulators, two clusters were identified by consensus clustering, in which cluster 1 had better overall survival (OS). A total of 4,429 DEGs were found between the two clusters, and were enriched into immune-related biological processes. Further analysis of the two clusters’ TME showed that cluster 1 had lower immune and ESTIMATE scores, higher expressions of HLA and lower expressions of immune checkpoint molecules. Besides, immune infiltration and the expressions of Th1/IFNγ gene signature also have significant differences between two clusters. Conclusions: Our study revealed that m6A regulators were important participants in the development of ccRCC, with a close relationship with TME.

scholarly journals Molecular Characterization and Clinical Relevance of m6A RNA Methylation Regulators in Cervical Cancer

2020 ◽  
Author(s):  
Jin Chen ◽  
Ji He ◽  
Xiaolei Ma ◽  
Xia Guo
Keyword(s):  
Cervical Cancer ◽  
Clinical Relevance ◽  
Cox Regression ◽  
Critical Role ◽  
The Cancer Genome Atlas ◽  
Rna Modification ◽  
Lasso Regression ◽  
Cox Regression Analysis ◽  
Rna Methylation ◽  
M6a Rna Methylation

Abstract Background: RNA modification, such as methylation of N6 adenosine (m6A), plays a critical role in many biological processes. However, the role of m6A RNA modification in cervical cancer (CC) remains largely unknown. Methods: The present study systematically investigated the molecular signatures and clinical relevance of 20 m6A RNA methylation regulators (writers, erasers, readers) in CC. The mRNA expression and clinical significance of m6A-related genes were investigated using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cervical cancer cohort. Mutations, copy number variation (CNV), differential expression, gene ontology analysis and the construction of a mRNA-microRNA regulatory network were performed to investigate the underlying mechanisms involved in the abnormal expression of m6A-related genes. Results: We found inclusive genetic information alterations among the m6A regulators and that their transcript expression levels were significantly associated with cancer hallmark-related pathways activity, such as the PI3K-AKT signaling pathway, microRNAs in cancer and the focal adhesion pathway, which were significantly enriched. Moreover, m6A regulators were found to be potentially useful for prognostic stratification and we identified FMR1 and ZC3H13 as potential prognostic risk oncogenes by LASSO regression. The ROC curves of 3, 5 and 10 years were 0.685, 0.726 and 0.741, respectively. The specificity for 3, 5 and 10 years were 0.598, 0.631 and 0.833, the sensitivity were 0.707, 0.752 and 0.811, respectively. Conclusions: Multivariable Cox regression analysis revealed that the risk score is an independent prognostic marker and can be used to predict the clinical and pathological features of CC.

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