Abstract
In mammals, cellular identity is defined through strict regulation of chromatin modifications and DNA methylation that control gene expression. Methylation of cytosines at CpG sites in the genome is mainly associated with suppression; however, the reason for enhancer-specific methylation is not fully understood. We used sequential ChIP-bisulfite-sequencing for H3K4me1 and H3K27ac histone marks. By collecting data from the same genomic region, we identified enhancers differentially methylated between these two marks. We observed a global gain of CpG methylation primarily in H3K4me1-marked nucleosomes during mouse embryonic stem cell differentiation. This gain occurred largely in enhancer regions that regulate genes critical for differentiation. The higher levels of DNA methylation in H3K4me1- versus H3K27ac-marked enhancers, despite it being the same genomic region, indicates cellular heterogeneity of enhancer states. Analysis of single-cell RNA-seq profiles demonstrated that this heterogeneity correlates with gene expression during differentiation. Furthermore, heterogeneity of enhancer methylation correlates with transcription start site methylation. Our results provide insights into enhancer-based functional variation in complex biological systems.
Highlights
Chromatin plasticity allows variation in transcriptional programs in cells with identical genetic codes
Enhancers are marked by two distinct chemical groups-H3K4me1 and H3K27ac on the tail of histones
As we measured the same genomic locations, we show that differences of DNA methylation between these marks can only be explained by cellular heterogeneity
Summary
Chromatin plasticity allows variation in transcriptional programs in cells with identical genetic codes. Cellular differentiation is regulated in part through modifications that decorate histone tails. Different modifications are associated with distinct genomic features such as active and repressive regions, distal elements, and promoters. The histone marks regulate access of transcription factors to the genome, and hundreds of chromatin regulators read, write, and erase these marks. H3K4me and H3K27ac are the main modifications of interest in this paper. H3K4me is situated on distal enhancer elements, whether they are poised or active. H3K27ac predominantly marks active promoters and enhancers. The two modifications label active enhancers [1,2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
