β-Catenin safeguards the ground state of mouse pluripotency by strengthening the robustness of the transcriptional apparatus
Research output: Contribution to journal › Journal article › Research › peer-review
Documents
- β-Catenin safeguards the ground state of mouse pluripotency by strengthening the robustness of the transcriptional apparatus
Final published version, 24.1 MB, PDF document
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 β-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 β-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 language | English |
---|---|
Article number | eaba1593 |
Journal | Science Advances |
Volume | 6 |
Issue number | 29 |
Number of pages | 17 |
ISSN | 2375-2548 |
DOIs | |
Publication status | Published - 2020 |
Number of downloads are based on statistics from Google Scholar and www.ku.dk
ID: 248461817