The epigenomics of embryonic stem cell differentiation

Abstract

Embryonic stem cells (ESCs) possess an open and highly dynamic chromatin landscape, which underlies their plasticity and ultimately maintains ESC pluripotency. The ESC epigenome must not only maintain the transcription of pluripotency-associated genes but must also, through gene priming, facilitate rapid and cell type-specific activation of developmental genes upon lineage commitment. Trans-generational inheritance ensures that the ESC chromatin state is stably transmitted from one generation to the next; yet at the same time, epigenetic marks are highly dynamic, reversible and responsive to extracellular cues. Once committed to differentiation, the ESC epigenome is remodeled and resolves into a more compact chromatin state. A thorough understanding of the role of chromatin modifiers in ESC fate and differentiation will be important if they are to be used for therapeutic purposes. Recent technical advances, particularly in next-generation sequencing technologies, have provided a genome-scale view of epigenetic marks and chromatin modifiers. More affordable and faster sequencing platforms have led to a comprehensive characterization of the ESC epigenome and epigenomes of differentiated cell types. In this review, we summarize and discuss the recent progress that has highlighted the central role of histone modifications, histone variants, DNA methylation and chromatin modifiers in ESC pluripotency and ESC fate. We provide a detailed and comprehensive discussion of genome-wide studies that are pertinent to our understanding of mammalian development.

Keywords: Epigenomics; chromatin; differentiation; embryonic stem cells.

Figure 1

Resolution of gene bivalency upon cell fate commitment. MLL and PcG complexes deposit H3K4me3 and H3K27me3 respectively at bivalent promoters. PRC1 binds to H3K27me3 marks, and via Ring1 ubiquitinates H2A. In ESCs, bivalent domains are found on numerous CpG-rich promoters. Poised RNA Pol II facilitates rapid activation upon presentation of developmental cues. Primed promoters may remain bivalent during differentiation or bivalency may resolve to monovalency.

Figure 2

Context-dependent roles of esBAF/Brg1 in ESC gene regulation. A: esBAF antagonizes PcG binding in order to potentiate LIF/STAT3 signaling. B: esBAF and PcG act synergistically in the repression of HOX genes. C: esBAF/Brg1 antagonizes Mbd3/NuRD and thereby fine-tunes gene expression levels.

Figure 3

Differential roles of H2A.Z in gene activation and repression, modulating self-renewal and differentiation of ESCs. H2A.Z facilitates chromatin accessibility by modulating nucleosome stability. In the undifferentiated state, H2A.Z allows pluripotency transcription factors such as Oct4 to bind to its target sites and thereby facilitate gene activation. At the same time, allowing PcG access to developmental genes modulates gene repression. Upon cell fate commitment, other master transcription factors require H2A.Z for accessibility to their targets.