Abstract:
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.
摘要:
DNA甲基化,一种改变基因表达而不改变DNA序列的表观遗传机制,对于生物体发育和关键的生物过程如基因组印迹和X染色体失活至关重要。尽管在DNA甲基化研究方面付出了巨大的努力,准确定量胞嘧啶甲基化仍然是一个挑战。这里,通过加权基因组区域中连续CpG位点的甲基化(Wemics)引入单碱基甲基化定量方法.Wemics对DNA甲基化的定量可以更好地预测其对基因转录的调节作用,并鉴定出具有更多生物学相关性的差异甲基化区域(DMRs)。肺癌中大多数Wemics定量DMRs是表观遗传保守的,并且在癌症基因组图谱(TCGA)的其他原发性癌症中反复出现。它们的异常改变可以作为有希望的泛癌症诊断标记。进一步揭示了这些检测到的DMRs富含转录因子(TF)结合基序,这些TF结合基序的甲基化和TF表达协同调节靶基因表达。使用Wemics对来自大型肺癌队列的表观基因组转录组数据,发现了12个具有致癌潜力的新基因,这些基因通过低甲基化被上调,但被其他定量方法所忽视。这些发现增加了对DNA甲基化调节基因表达的表观遗传机制的理解。