Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Department of Respiratory Medicine, Department of Clinical Laboratory, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China.
Institute of Bioinformatics, Zhejiang University, Hangzhou, 310058, China.
Adv Sci (Weinh). 2024 Jun;11(21):e2308884. doi: 10.1002/advs.202308884. Epub 2024 Mar 28.
DNA methylation, an epigenetic mechanism that alters gene expression without changing DNA sequence, is essential for organism development and key biological processes like genomic imprinting and X-chromosome inactivation. Despite tremendous efforts in DNA methylation research, accurate quantification of cytosine methylation remains a challenge. Here, a single-base methylation quantification approach is introduced by weighting methylation of consecutive CpG sites (Wemics) in genomic regions. Wemics quantification of DNA methylation better predicts its regulatory impact on gene transcription and identifies differentially methylated regions (DMRs) with more biological relevance. Most Wemics-quantified DMRs in lung cancer are epigenetically conserved and recurrently occurred in other primary cancers from The Cancer Genome Atlas (TCGA), and their aberrant alterations can serve as promising pan-cancer diagnostic markers. It is further revealed that these detected DMRs are enriched in transcription factor (TF) binding motifs, and methylation of these TF binding motifs and TF expression synergistically regulate target gene expression. Using Wemics on epigenomic-transcriptomic data from the large lung cancer cohort, a dozen novel genes with oncogenic potential are discovered that are upregulated by hypomethylation but overlooked by other quantification methods. These findings increase the understanding of the epigenetic mechanism by which DNA methylation regulates gene expression.
DNA 甲基化是一种表观遗传机制，它可以在不改变 DNA 序列的情况下改变基因表达，对生物体的发育和基因组印迹、X 染色体失活等关键生物学过程至关重要。尽管在 DNA 甲基化研究方面付出了巨大努力，但对胞嘧啶甲基化的准确定量仍然是一个挑战。本研究提出了一种基于连续 CpG 位点（Wemics）加权的基因组区域单碱基甲基化定量方法。Wemics 定量的 DNA 甲基化能更好地预测其对基因转录的调控作用，并能识别出具有更高生物学相关性的差异甲基化区域（DMRs）。在肺癌中，大多数 Wemics 定量的 DMRs 是表观遗传保守的，并且在 TCGA 中的其他原发性癌症中经常发生，其异常改变可以作为有前途的泛癌诊断标志物。进一步研究表明，这些检测到的 DMRs 富集在转录因子（TF）结合基序中，TF 结合基序的甲基化和 TF 表达协同调节靶基因的表达。利用大规模肺癌队列的表观基因组-转录组数据进行 Wemics 分析，发现了十几个具有致癌潜力的新基因，它们的上调是由低甲基化引起的，但被其他定量方法所忽略。这些发现增加了对 DNA 甲基化调控基因表达的表观遗传机制的理解。
