@article{749cbda4bb3941a68d3279fa876352b8,
title = "beta-Catenin safeguards the ground state of mouse pluripotency by strengthening the robustness of the transcriptional apparatus",
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.",
author = "Meng Zhang and Yiwei Lai and Vladislav Krupalnik and Pengcheng Guo and Xiangpeng Guo and Jianguo Zhou and Yan Xu and Zhijun Yu and Longqi Liu and Ao Jiang and Wenjuan Li and Gang Ma and Na Li and Xiuling Fu and Yuan Lv and Mengling Jiang and Muqddas Tariq and Shahzina Kanwal and Hao Liu and Xueting Xu and Hui Zhang and Yinghua Huang and Lulu Wang and Shuhan Chen and Babarinde, {Isaac A.} and Zhiwei Luo and Dongye Wang and Tiantian Zhou and Carl Ward and Minghui He and Ibanez, {David P.} and Yunpan Li and Jiajian Zhou and Jie Yuan and Yayan Feng and Karthik Arumugam and {Di Vicino}, Umberto and Xichen Bao and Guangming Wu and Axel Schambach and Huating Wang and Hao Sun and Fei Gao and Baoming Qin and Hutchins, {Andrew P.} and Doble, {Bradley W.} and Christine Hartmann and Cosma, {Maria Pia} and Yan Qin and Guo-Liang Xu and Runsheng Chen and Giacomo Volpe and Liang Chen and Hanna, {Jacob H.} and Esteban, {Miguel A.}",
note = "We thank all members of the Esteban laboratory for their comments. We also thank M. Oren (Weizmann Institute of Science, Israel) for technical advice and J. T. Lis (Cornell University, USA) and X. Fu (University of California, USA) for helpful comments on this manuscript. We also thank the technical support from the Guangzhou Branch of the Supercomputing Center of Chinese Academy of Science and the Experimental Animal Center of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences. Funding: This work was supported by the National Key Research and Development Program of China (2016YFA0100102, 2016YFA0100701, 2016YFA0100300, and 2018YFA0106903), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030502), the National Natural Science Foundation of China (31671537, 31571524, 31501192, 31430049, 31850410463, 31970619, 31950410553, and 31900617), the Guangdong Province Science and Technology Program (2014A030312001, 2015A030308007, 2016B030229007, 2016A050503037, and 2017B050506007), the Guangzhou Science and Technology Program (201807010066), the Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110103001), and the Science and Technology Planning Project of Guangdong Province, China (2017B030314056). J.H.H. was funded by Pascal and Ilana Mantoux, Helen and Martin Kimmel Institute for Stem Cell Research, Flight Attendant Medical Research Council (FAMRI), European Research Council (ERC-CoG), and an Israel-China Israel Science Foundation (ISF) grant. C.W. was supported by a Zhujiang Overseas Young Talents Postdoctoral Fellowship. S.K. was supported by a Chinese Academy of Sciences President{\textquoteright}s International Fellowship. M.M.A., D.P.I., and M.T. were supported by the Chinese Academy of Sciences–Third World Academy of Sciences (TWAS) President{\textquoteright}s PhD Fellowship. A.S. was supported by the Deutsche Forschungsgemeinschaft (REBIRTH and SFB738). Author contributions: M.A.E., M.Z., and Y. Lai conceived the idea and designed the experiments. M.Z. conducted most of the experiments and Y. Lai performed most of the bioinformatics study. M.A.E., M.Z., and Y. Lai analyzed the data. V.K. and L.C. contributed critically to the experiments. P.G., X.G., Jianguo Zhou, Y.X., Z.Y., L.L., A.J., W.L., M.M.A., G.M., N.L., X.F., Y. Lv., M.J., M.T., S.K., H.L., X.X., H.Z., Y.H., L.W., S.C., I.A.B., Z.L., D.W., T.Z., C.W., M.H., D.P.I., Y. Li, Jiajian Zhou, J.Y., Y.F., K.A., U.D.V., F.G., A.P.H., and G.V. contributed to the experiments and/or the analyses. X.B., G.W., A.S., H.W., H.S., B.Q., A.P.H., B.W.D., C.H., M.P.C., Y.Q., G.-L.X., R.C., and G.V. provided relevant advice, essential materials, and/or infrastructural support. M.A.E. supervised the study and provided most of the financial support. J.H.H. contributed to the supervision and also provided financial support. M.A.E. wrote the manuscript with help from M.Z. and Y. Lai. M.A.E. approved the final version of the manuscript.",
year = "2020",
month = jul,
day = "15",
doi = "https://doi.org/10.1126/sciadv.aba1593",
language = "الإنجليزيّة",
volume = "6",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "29",
}