Recent studies have shown that N6-methyladenosine (m6A) plays a critical role in numbers of biological processes and complex human diseases. However, the regulatory mechanisms of most methylation sites remain uncharted. Thus, in-depth study of the epi-transcriptomic patterns of m6A may provide insights into its complex functional and regulatory mechanisms. Due to the high economic and time cost of wet experimental methods, revealing methylation patterns through computational models has become a more preferable way, and drawn more and more attention. Considering the theoretical basics and applications of conventional clustering methods, an RNA Expression Weighted Iterative Signature Algorithm (REW-ISA) is proposed to find potential local functional blocks (LFBs) based on MeRIP-Seq data, where sites are hyper-methylated or hypo-methylated simultaneously across the specific conditions. REW-ISA adopts RNA expression levels of each site as weights to make sites of lower expression level less significant. It starts from random sets of sites, then follows iterative search strategies by thresholds of rows and columns to find the LFBs in m6A methylation profile. Its application on MeRIP-Seq data of 69,446 methylation sites under 32 experimental conditions unveiled 6 LFBs, which achieve higher enrichment scores than ISA. Pathway analysis and enzyme specificity test showed that sites remained in LFBs are highly relevant to the m6A methyltransferase, such as METTL3, METTL14, WTAP and KIAA1429. Further detailed analyses for each LFB even showed that some LFBs are condition-specific, indicating that methylation profiles of some specific sites may be condition relevant. REW-ISA finds potential local functional patterns presented in m6A profiles, where sites are co-methylated under specific conditions.

中文翻译：

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REW-ISA：通过RNA表达加权迭代签名算法在转录组分析数据中揭示局部功能模块

最近的研究表明，N6-甲基腺苷（m6A）在许多生物过程和复杂的人类疾病中起着至关重要的作用。但是，大多数甲基化位点的调节机制仍然未知。因此，对m6A的转录组模式的深入研究可能会提供有关其复杂功能和调节机制的见解。由于湿法实验方法的经济和时间成本高，通过计算模型揭示甲基化模式已成为一种更可取的方法，并受到越来越多的关注。考虑到常规聚类方法的理论基础和应用，提出了一种RNA表达加权迭代签名算法（REW-ISA），用于基于MeRIP-Seq数据查找潜在的局部功能块（LFB），在特定条件下，网站同时被高甲基化或低甲基化。REW-ISA采用每个位点的RNA表达水平作为权重，以使较低表达水平的位点的重要性降低。它从站点的随机集合开始，然后按照行和列的阈值遵循迭代搜索策略，以在m6A甲基化配置文件中查找LFB。它在32个实验条件下的69,446个甲基化位点的MeRIP-Seq数据上的应用揭示了6个LFB，其富集得分高于ISA。路径分析和酶特异性测试表明，LFB中残留的位点与m6A甲基转移酶高度相关，例如METTL3，METTL14，WTAP和KIAA1429。对每个LFB的进一步详细分析甚至表明，某些LFB是特定于条件的，表明某些特定位点的甲基化分布可能与条件有关。REW-ISA发现了m6A配置文件中显示的潜在局部功能模式，其中位点在特定条件下被共甲基化。