beta-Catenin safeguards the ground state of mouse pluripotency by strengthening the robustness of the transcriptional apparatus

Meng Zhang, Yiwei Lai, Vladislav Krupalnik, Pengcheng Guo, Xiangpeng Guo, Jianguo Zhou, Yan Xu, Zhijun Yu, Longqi Liu, Ao Jiang, Wenjuan Li, Gang Ma, Na Li, Xiuling Fu, Yuan Lv, Mengling Jiang, Muqddas Tariq, Shahzina Kanwal, Hao Liu, Xueting XuHui Zhang, Yinghua Huang, Lulu Wang, Shuhan Chen, Isaac A. Babarinde, Zhiwei Luo, Dongye Wang, Tiantian Zhou, Carl Ward, Minghui He, David P. Ibanez, Yunpan Li, Jiajian Zhou, Jie Yuan, Yayan Feng, Karthik Arumugam, Umberto Di Vicino, Xichen Bao, Guangming Wu, Axel Schambach, Huating Wang, Hao Sun, Fei Gao, Baoming Qin, Andrew P. Hutchins, Bradley W. Doble, Christine Hartmann, Maria Pia Cosma, Yan Qin, Guo-Liang Xu, Runsheng Chen, Giacomo Volpe, Liang Chen, Jacob H. Hanna, Miguel A. Esteban

Research output: Contribution to journalArticlepeer-review

Abstract

Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. We show that B-catenin, stabilized by GSK3 inhibition in medium with 2i, supplies transcriptional coregulators at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by beta-catenin, and proliferation/self-renewal remains tightly controlled by Pol2 pause release under 2i conditions. Our findings explain how pluripotency is reinforced in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other contexts.

Original languageEnglish
Article number1593
Number of pages16
JournalScience Advances
Volume6
Issue number29
DOIs
StatePublished - 15 Jul 2020

All Science Journal Classification (ASJC) codes

  • General

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