Integrative single-cell omics analyses reveal epigenetic heterogeneity in mouse embryonic stem cells

Area of Science:

• Epigenetics
• Stem Cell Biology
• Computational Biology

Background:

• Embryonic stem cells (ESCs) exhibit significant heterogeneity.
• Epigenetic mechanisms driving ESC heterogeneity are poorly understood.
• Identifying cell-subset specific methylation and its biological significance is challenging.

Purpose of the Study:

• To develop a computational pipeline for single-cell methylome and transcriptome analysis.
• To identify and interpret cell-subset specific methylation (CSM) loci in ESCs.
• To explore the relationship between DNA methylation and gene expression heterogeneity.

Main Methods:

• Implementation of a computational pipeline for single-cell methylome analysis.
• Integrative analysis of single-cell methylome and transcriptome data.
• Application of a beta mixture model to infer cell-subset specific methylation (CSM) loci.

Main Results:

• Identified putative CSM loci enriched in CpG island shelves and regulatory regions.
• Genes associated with CSM loci display wide-ranging expression patterns in ESCs.
• Discovered co-methylated modules linked to transcription factor binding motifs.

Conclusions:

• The developed tool enables exploration of single-cell epigenomic and transcriptomic data.
• Provides insights into transcriptional regulatory networks underlying ESC epigenetic heterogeneity.
• Advances understanding of DNA methylation's role in cell-to-cell variation within stem cell populations.