DNA methylation is an important epigenetic mark that plays a vital role in gene expression and cell differentiation. The average DNA methylation level among a group of cells has been extensively documented. However, the cell-to-cell heterogeneity in DNA methylation, which reflects the differentiation of epigenetic status among cells, remains less investigated. Here we established a gold standard of the cell-to-cell heterogeneity in DNA methylation based on single-cell bisulfite sequencing (BS-seq) data. With that, we optimized a computational pipeline for estimating the heterogeneity in DNA methylation from bulk BS-seq data. We further built HeteroMeth, a database for searching, browsing, visualizing, and downloading the data for heterogeneity in DNA methylation for a total of 141 samples in humans, mice, Arabidopsis, and rice. Three genes are used as examples to illustrate the power of HeteroMeth in the identification of unique features in DNA methylation. The optimization of the computational strategy and the construction of the database in this study complement the recent experimental attempts on single-cell DNA methylomes and will facilitate the understanding of epigenetic mechanisms underlying cell differentiation and embryonic development. HeteroMeth is publicly available at http://qianlab.genetics.ac.cn/HeteroMeth.
DNA甲基化作为一个重要的表观调控因子，在基因表达调控和细胞分化的过程中发挥着至关重要的作用。研究者通常以细胞群体作为一个整体，基于这群细胞的平均DNA甲基化水平开展分析。值得注意的是，不同细胞之间DNA甲基化修饰并非均一，而这种异质性可能反映了细胞间表观修饰状态的分化。但是目前关于单细胞DNA甲基化修饰异质性的研究还鲜见报道。我们基于单细胞亚硫酸氢盐测序数据，为计算单细胞DNA甲基化异质性建立了金标准，进而优化了从细胞群体样品亚硫酸氢盐测序数据中计算单细胞DNA甲基化异质性的策略，并搭建了HeteroMeth数据库。该数据库提供了来自人类、小鼠、拟南芥和水稻共141个样品的DNA甲基化异质性数据，可以方便得进行查找、浏览、可视化和下载。此研究中计算策略的优化和数据库的建立，将推动DNA甲基化修饰异质性特征的系统识别，从而为细胞分化和胚胎发育过程中表观调控机制的探索提供关键性的支持。HeteroMeth的公共链接地址为：http://qianlab.genetics.ac.cn/HeteroMeth。





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