Abstract
Transcription factor networks, together with histone modifications and signalling pathways, underlie the establishment and maintenance of gene regulatory architectures associated with the molecular identity of each cell type. However, how master transcription factors individually impact the epigenomic landscape and orchestrate the behaviour of regulatory networks under different environmental constraints is only partially understood. Here, we show that the transcription factor Nanog deploys multiple distinct mechanisms to enhance embryonic stem cell self-renewal. In the presence of LIF, which fosters self-renewal, Nanog rewires the pluripotency network by promoting chromatin accessibility and binding of other pluripotency factors to thousands of enhancers. In the absence of LIF, Nanog blocks differentiation by sustaining H3K27me3, a repressive histone mark, at developmental regulators. Among those, we show that the repression of Otx2 plays a preponderant role. Our results underscore the versatility of master transcription factors, such as Nanog, to globally influence gene regulation during developmental processes.
Highlights
Transcription factor networks, together with histone modifications and signalling pathways, underlie the establishment and maintenance of gene regulatory architectures associated with the molecular identity of each cell type
We reveal different modes and the varied logic employed by Nanog to orchestrate the three main features associated with self-renewal: the inter-dependencies between pluripotency transcription factors (TFs), LIF signalling, and bivalent chromatin domains
We found that the increase of Nanog expression was due to both stronger and more frequent transcriptional bursts (Fig. 1d and Supplementary Fig. 1H, I)
Summary
Transcription factor networks, together with histone modifications and signalling pathways, underlie the establishment and maintenance of gene regulatory architectures associated with the molecular identity of each cell type. The key properties of TF networks, shared among cell types, developmental contexts and organisms[3], are exemplified by the pluripotency network, which plays a dominant role during early mammalian embryogenesis[4] The robustness of this network allows to capture the ex vivo of transient biological identity of the pluripotent epiblast through the derivation of self-renewing Embryonic Stem (ES) cells[5], which have enabled identification of key TFs (e.g., Oct[4], Sox[2], Nanog and Esrrb). A key function of the pluripotency network is to integrate signalling cues to appropriately respond to changes in the environment, conferring the responsiveness of ES cells and their capacity to readily differentiate In this regard, it is noteworthy that Nanog was first identified as a factor capable of bypassing the requirements for LIF: in the presence of ectopic Nanog expression, ES cell self-renewal is strongly enhanced and completely independent of LIF14. We reveal different modes and the varied logic employed by Nanog to orchestrate the three main features associated with self-renewal: the inter-dependencies between pluripotency TFs, LIF signalling, and bivalent chromatin domains
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