Esrrb Unlocks Silenced Enhancers for Reprogramming to Naive Pluripotency

Publication date: Available online 14 June 2018
Source:Cell Stem Cell
Author(s): Kenjiro Adachi, Wolfgang Kopp, Guangming Wu, Sandra Heising, Boris Greber, Martin Stehling, Marcos J. Araúzo-Bravo, Stefan T. Boerno, Bernd Timmermann, Martin Vingron, Hans R. Schöler
Transcription factor (TF)-mediated reprogramming to pluripotency is a slow and inefficient process, because most pluripotency TFs fail to access relevant target sites in a refractory chromatin environment. It is still unclear how TFs actually orchestrate the opening of repressive chromatin during the long latency period of reprogramming. Here, we show that the orphan nuclear receptor Esrrb plays a pioneering role in recruiting the core pluripotency factors Oct4, Sox2, and Nanog to inactive enhancers in closed chromatin during the reprogramming of epiblast stem cells. Esrrb binds to silenced enhancers containing stable nucleosomes and hypermethylated DNA, which are inaccessible to the core factors. Esrrb binding is accompanied by local loss of DNA methylation, LIF-dependent engagement of p300, and nucleosome displacement, leading to the recruitment of core factors within approximately 2 days. These results suggest that TFs can drive rapid remodeling of the local chromatin structure, highlighting the remarkable plasticity of stable epigenetic information.

Graphical abstract

Teaser

Rapid reprogramming of epiblast stem cells (EpiSCs) to induced pluripotent stem cells (iPSCs) allows a detailed analysis of epigenetic remodeling induced by transcription factors. The orphan nuclear receptor Esrrb plays a pioneering role in establishing a permissive chromatin environment for the recruitment of core pluripotency factors Oct4, Sox2, and Nanog.


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