Identification and experimental validation of key m6A modification regulators as potential biomarkers of osteoporosis.
Identification and experimental validation of key m6A modification regulators as potential biomarkers of osteoporosis.
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DOI：
10.3389/fgene.2022.1072948
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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骨质疏松症(OP)是一种严重的全身性骨代谢疾病，在全世界范围内都有发生。在冠状病毒大流行期间，紧急服务的优先次序和选择性护理的延误削弱了对OP患者的常规筛查和监测。迫切需要新的和有效的筛查诊断生物标记物，需要最少的技术和时间投资。一些研究表明，N6-甲基腺苷(M6A)调节剂在包括OP在内的代谢性疾病中发挥着重要作用。本研究的目的是通过基因表达数据分析和实验验证，确定关键的m6A调节因子作为OP的生物标志物。GSE56815数据集作为40名高骨密度女性和40名低骨密度女性的训练数据集。分析14个主要的M6A调节因子的表达水平，以筛选两组中差异表达的M6A调节因子。探讨m6A修饰对骨代谢微环境特征的影响，包括成骨细胞相关基因和破骨细胞相关基因集。大多数m6A调节基因和骨代谢相关基因集在低骨密度样本中表达失调，它们之间的关系也密切相关。此外，还进行了共识聚类分析，在低骨密度样本中发现了两种不同的m6A修饰模式。随后，通过单变量和多变量Logistic回归分析，我们确定了四个关键的M6A调控基因，即METTL16、CBLL1、FTO和YTHDF2。我们构建了一个基于四个M6A调节器的诊断模型。CBLL1和YTHDF2是保护因素，而METTL16和FTO是危险因素，ROC曲线和测试数据集验证了该模型在区分高和低骨密度样本方面具有中等的准确性。此外，构建了由4个HUB M6A调控基因和26个M6A靶向骨代谢相关基因组成的调控网络，加深了我们对M6A修饰在OP中的调控机制的理解。最后，对四个关键的M6A调控因子进行了体内和体外的表达验证，结果与生物信息学分析结果一致。我们的发现确定了四个关键的M6A调节因子，它们对骨代谢是必不可少的，并且在OP中具有特殊的诊断价值。这些模块可作为未来OP的生物标志物。
Osteoporosis (OP) is a severe systemic bone metabolic disease that occurs worldwide. During the coronavirus pandemic, prioritization of urgent services and delay of elective care attenuated routine screening and monitoring of OP patients. There is an urgent need for novel and effective screening diagnostic biomarkers that require minimal technical and time investments. Several studies have indicated that N6-methyladenosine (m6A) regulators play essential roles in metabolic diseases, including OP. The aim of this study was to identify key m6A regulators as biomarkers of OP through gene expression data analysis and experimental verification. GSE56815 dataset was served as the training dataset for 40 women with high bone mineral density (BMD) and 40 women with low BMD. The expression levels of 14 major m6A regulators were analyzed to screen for differentially expressed m6A regulators in the two groups. The impact of m6A modification on bone metabolism microenvironment characteristics was explored, including osteoblast-related and osteoclast-related gene sets. Most m6A regulators and bone metabolism-related gene sets were dysregulated in the low-BMD samples, and their relationship was also tightly linked. In addition, consensus cluster analysis was performed, and two distinct m6A modification patterns were identified in the low-BMD samples. Subsequently, by univariate and multivariate logistic regression analyses, we identified four key m6A regulators, namely, METTL16, CBLL1, FTO, and YTHDF2. We built a diagnostic model based on the four m6A regulators. CBLL1 and YTHDF2 were protective factors, whereas METTL16 and FTO were risk factors, and the ROC curve and test dataset validated that this model had moderate accuracy in distinguishing high- and low-BMD samples. Furthermore, a regulatory network was constructed of the four hub m6A regulators and 26 m6A target bone metabolism-related genes, which enhanced our understanding of the regulatory mechanisms of m6A modification in OP. Finally, the expression of the four key m6A regulators was validated in vivo and in vitro, which is consistent with the bioinformatic analysis results. Our findings identified four key m6A regulators that are essential for bone metabolism and have specific diagnostic value in OP. These modules could be used as biomarkers of OP in the future.
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影响因子：
12.7
作者：
Yao GQ;Troiano N;Simpson CA;Insogna KL
通讯作者：
Insogna KL
影响因子：
4.2
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Camacho, Pauline M.
DOI：
10.1016/j.bbadis.2018.09.015
发表时间：
2018-12-01
影响因子：
6.2
作者：
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通讯作者：
Xu, You-Jia