Abstract
Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in a concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate.
Highlights
Embryonic stem cells (ESC) are pluripotent cells that have the potential to self-renew indefinitely and to differentiate into any of the three germ layers
Using a wide array of statistical approaches we show that changes in histone acetylation are very predictive for gene expression and that the concordance between the two levels increases over time
Concentrating on genes central to the regulatory networks in embryonic stem cells we find that key genes show very high acetylation signal in the beginning that decreases quickly over time, indicating that they lie in initially open regions that are rapidly closing down
Summary
Embryonic stem cells (ESC) are pluripotent cells that have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. Molecular regulation of embryonic stem cell fate is implemented by a coordinated interaction between epigenetic [1,2,3,4,5], transcriptional [6,7,8,9,10,11] and translational [12,13] mechanisms. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood [14], but recent results point to key roles for a network of transcription factors [9,15,16] and a wide range of epigenetic mechanisms [2,17,18,19]. Bivalent domains – consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation– silence developmental genes in ES cells while keeping them poised for action [1,3]
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