The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells

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.

Endogenous fluctuations of OCT 4 and SOX 2 bias pluripotent cell fate decisions

“…Accordingly, NANOG binding was strongly enriched at loci whose accessibility was upregulated in OCT4‐high or SOX2‐high cells compared to regions with downregulated accessibility (Fig EV5N). This suggests that NANOG may act as a binding partner to regulate chromatin accessibility at these loci, in line with a recent study (Heurtier et al , ). Loci with increased accessibility in OCT4‐high cells lose accessibility upon rapid OCT4 depletion (data from King & Klose, ), in line with OCT4 directly regulating accessibility at these sites (Fig EV5O) even though we cannot exclude that some loci may be regulated by indirect mechanisms.…”

“…Using thousands of ChIP‐seq datasets in ES cells, we could train a model to predict, with relatively good accuracy, regions that were upregulated or downregulated in accessibility upon high levels of OCT4 or SOX2 (Fig EV5M). We identified NANOG binding as enriched in upregulated regions, consistent with a recent report on the impact of NANOG depletion on OCT4/SOX2 binding and accessibility (Heurtier et al , ). However, we could not find features allowing to predict whether loci are more dependent on OCT4 versus SOX2.…”

HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors

“…To validate preliminary NANOG-responsive genes from this analysis, we further performed a complementary analysis followed by filtering to include only genes that have been previously identified as responding to NANOG [34][35][36][37][38] . Subsequently, we acquired the refined NANOG-responsive six genes (FGFBP1, SPESP1, HMGA2, PERP, FGF1, and DKK1).…”

Segregation of the mouse germline and soma

“…In common with some other pluripotency TFs expressed in naïve pre-implantation cells, NANOG is not expressed during peri-implantation development [15,38], nor in EpiLCs [12,28]. Previous work has demonstrated that NANOG and OTX2 work antagonistically in ESCs [27,39] and OTX2 has been shown to be robustly expressed in both EpiLCs and the peri-implantation epiblast [17,24]. However, OTX2 is not responsible for ongoing repression of Nanog in EpiLCs [17].…”