期刊
SCIENCE ADVANCES
卷 6, 期 29, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aba1593
关键词
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资金
- National Key Research and Development Program of China [2016YFA0100102, 2016YFA0100701, 2016YFA0100300, 2018YFA0106903]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16030502]
- National Natural Science Foundation of China [31671537, 31571524, 31501192, 31430049, 31850410463, 31970619, 31950410553, 31900617]
- Guangdong Province Science and Technology Program [2014A030312001, 2015A030308007, 2016B030229007, 2016A050503037, 2017B050506007]
- Guangzhou Science and Technology Program [201807010066]
- Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory [2018GZR110103001]
- Science and Technology Planning Project of Guangdong Province, China [2017B030314056]
- Flight Attendant Medical Research Council (FAMRI)
- European Research Council (ERC-CoG)
- Israel-China Israel Science Foundation (ISF) grant
- Zhujiang Overseas Young Talents Postdoctoral Fellowship
- Chinese Academy of Sciences President's International Fellowship
- Chinese Academy of Sciences-Third World Academy of Sciences (TWAS) President's PhD Fellowship
- Deutsche Forschungsgemeinschaft [SFB738]
- Helen and Martin Kimmel Institute for Stem Cell Research
- Deutsche Forschungsgemeinschaft (REBIRTH)
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.
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