Abstract
Embryonic stem cells (ESCs) consist of a population of self-renewing cells displaying extensive phenotypic and functional heterogeneity. Research towards the understanding of the epigenetic mechanisms underlying the heterogeneity among ESCs is still in its initial stage. Key issues, such as how to identify cell-subset specifically methylated loci and how to interpret the biological meanings of methylation variations remain largely unexplored. To fill in the research gap, we implemented a computational pipeline to analyze single-cell methylome and to perform an integrative analysis with single-cell transcriptome data. According to the origins of variation in DNA methylation, we determined the genomic loci associated with allelic-specific methylation or asymmetric DNA methylation, and explored a beta mixture model to infer the genomic loci exhibiting cell-subset specific methylation (CSM). We observed that the putative CSM loci in ESCs are significantly enriched in CpG island (CGI) shelves and regions with histone marks for promoter and enhancer, and the genes hosting putative CSM loci show wide-ranging expression among ESCs. More interestingly, the putative CSM loci may be clustered into co-methylated modules enriching the binding motifs of distinct sets of transcription factors. Taken together, our study provided a novel tool to explore single-cell methylome and transcriptome to reveal the underlying transcriptional regulatory networks associated with epigenetic heterogeneity of ESCs.
Highlights
Embryonic stem cells (ESCs) have a wide range of applications in both basic research and preclinical drug screening
Methylation profiles of allele-specific DNA methylation (ASM) and asymmetric methylation (AM) loci in single-cell methylomes derived from mouse ESCs
To assess DNA methylation variations within and across single cells, we started with the scBS-Seq data generated with the random priming method for nineteen mouse ESCs [15]
Summary
Embryonic stem cells (ESCs) have a wide range of applications in both basic research and preclinical drug screening. Growing evidence indicated that heterogeneous ESCs display substantial variations in gene expression [5], transcription factor regulation patterns [6, 7], and epigenetic modifications including DNA methylation [8]. The heterogeneous expression of transcription factors (TFs) is responsible for lineage specific differentiation [9] and may underlie the mechanism that allows ESCs to exit self-renewal cycle and enter into various differentiation paths [7]. The interplays between TF binding and DNA methylation orchestrate gene expression. Despite these increased understandings, the connections among TF binding, DNA methylation, and gene expression in ESCs remain largely unexplored at the single-cell level
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