DNA methylation patterns expose variations in enhancer-chromatin modifications during embryonic stem cell differentiation

Autoři: Adi Alajem aff001;  Hava Roth aff001;  Sofia Ratgauzer aff001;  Danny Bavli aff001;  Alex Motzik aff001;  Shlomtzion Lahav aff001;  Itay Peled aff001;  Oren Ram aff001
Působiště autorů: Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel aff001
Vyšlo v časopise: DNA methylation patterns expose variations in enhancer-chromatin modifications during embryonic stem cell differentiation. PLoS Genet 17(4): e1009498. doi:10.1371/journal.pgen.1009498
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009498


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.

Klíčová slova:

Cell differentiation – DNA methylation – Gene expression – Gene regulation – Histones – Chromatin – Mammalian genomics – Methylation


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