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

作者全名："Ye, Fei; Wang, Tianzhu; Wu, Xiaoxin; Liang, Jie; Li, Jiaoxing; Sheng, Wenli"

作者地址："[Ye, Fei; Wu, Xiaoxin; Liang, Jie; Li, Jiaoxing; Sheng, Wenli] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Neurol, Guangzhou, Peoples R China; [Ye, Fei; Liang, Jie; Sheng, Wenli] Sun Yat Sen Univ, Affiliated Hosp 1, Guangdong Prov Key Lab Diag & Treatment Major Neu, Guangzhou, Peoples R China; [Wang, Tianzhu] Chongqing Med Univ, Dept Neurol, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："Sheng, WL (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 1, Dept Neurol, Guangzhou, Peoples R China."

来源：JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000678869700001

JCR分区：Q1

影响因子：7.4

年份：2021

卷号：19

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Progressive multiple sclerosis (PMS); N6-methyladenosine (m6A); Cerebrospinal fluid (CSF); Diagnostic biomarker

摘要："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."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81671132, 81471180, 82071286]"

基金资助正文："This study was supported by the National Natural Science Foundation of China (Nos. 81671132, 81471180, and 82071286)."