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Researchers found a new transcriptional mechanism regulating mouse ground state pluripotency

Mouse embryonic stem cells (ESCs) cultured with MEK and GSK3 inhibitors [2i (PD0325901 and CHIR99021) plus LIF, 2iL] more closely resemble the inner cell mass of preimplantation blastocysts than those cultured in SL (serum plus LIF).
Although ESCs in these two states share most characteristics, ESCs in 2iL are believed to be more resistant to network perturbation. This suggests a rewiring of the transcriptional/epigenetic regulatory networks that confers additional robustness in 2iL, but the underlying mechanisms remain unclear.
In a study published online in Science Advances, the researchers from the Guangzhou Institutes of Biomedicine and Health of the Chinese Academy of Sciences, and the collaborators, demonstrated new transcriptional mechanism regulating mouse ground state pluripotency. 

The researchers reported that, in 2iL, β-catenin supplies transcriptional co-regulators at pluripotency loci. This selectively strengthens these loci, rendering them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release mediated by the master regulators BRD4 and CDK9. In contrast, self-renewal/proliferation is highly dependent on Pol2 pause release and, hence, sensitive to BRD4/CDK9 inhibition in both conditions.  

These findings help to explain how pluripotency gene transcription is selectively reinforced in the ground state to protect against exogenous perturbation. 

To explore whether the link between Wnt/β-catenin signaling, transcription initiation, and BRD4 inhibitor resistance applies to other contexts, particularly cancer, the researchers tested this phenomenon in a widely used leukemia cell line called THP1. They found that Wnt activation also induced resistance to BRD4 inhibitor in THP1 cells, which also became more sensitive to transcription initiation inhibition.  

This study explains how mouse pluripotency is reinforced in the ground state and also provides a general model for transcriptional resilience/adaptation upon network perturbation in other contexts, especially in cancer.  


A model showing transcriptional mechanism of pluripotency genes in SL and 2iL. 


Miguel A. Esteban, Ph.D, Principle Investigator  

E-mail: miguel@gibh.ac.cn 

Link https://advances.sciencemag.org/content/6/29/eaba1593