2. Academic Validation
  3. β-Catenin safeguards the ground state of mousepluripotency by strengthening the robustness of the transcriptional apparatus

β-Catenin safeguards the ground state of mousepluripotency by strengthening the robustness of the transcriptional apparatus

  • Sci Adv. 2020 Jul 17;6(29):eaba1593. doi: 10.1126/sciadv.aba1593.
Meng Zhang 1 2 3 4 5 6,  Yiwei Lai 1 2 3 4 5 6,  Vladislav Krupalnik 7,  Pengcheng Guo 1 2 3 6 8,  Xiangpeng Guo 1 2 3 5 6,  Jianguo Zhou 1 2 3 6,  Yan Xu 1 2 3,  Zhijun Yu 1 2 3,  Longqi Liu 1 2 3,  Ao Jiang 9,  Wenjuan Li 5 6 10,  Mazid Md Abdul 1 2 3 4 5 6,  Gang Ma 2 3 11,  Na Li 1 2 3 6,  Xiuling Fu 12,  Yuan Lv 1 2 3 4 6,  Mengling Jiang 1 2 3 6,  Muqddas Tariq 1 2 3 4 6,  Shahzina Kanwal 1 2 3 6,  Hao Liu 1 2 3 6,  Xueting Xu 2 3 11,  Hui Zhang 2 3 5 11,  Yinghua Huang 2 3 5 11,  Lulu Wang 2 3 4 5 11,  Shuhan Chen 1 2 3 4 6,  Isaac A Babarinde 12,  Zhiwei Luo 5 6 10,  Dongye Wang 1 2 3 6,  Tiantian Zhou 13,  Carl Ward 1 2 3 5 6,  Minghui He 14,  David P Ibañez 1 2 3 4 6,  Yunpan Li 1 2 3 6,  Jiajian Zhou 15,  Jie Yuan 15,  Yayan Feng 16,  Karthik Arumugam 17 18,  Umberto Di Vicino 17 18,  Xichen Bao 1 2 3 5,  Guangming Wu 5,  Axel Schambach 19 20,  Huating Wang 21,  Hao Sun 15,  Fei Gao 16 22,  Baoming Qin 2 3 5 6 11,  Andrew P Hutchins 12,  Bradley W Doble 23,  Christine Hartmann 24,  Maria Pia Cosma 2 3 5 17 18 25,  Yan Qin 4 26 27,  Guo-Liang Xu 13 28,  Runsheng Chen 26,  Giacomo Volpe 1 2 3 5 6,  Liang Chen 9,  Jacob H Hanna 7,  Miguel A Esteban 1 2 3 5 6 29
Affiliations

Affiliations

  • 1 Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2 CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 3 Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.
  • 6 Joint School of Life Sciences, Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 511436, China.
  • 7 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 8 College of Veterinary Medicine, Jilin University, Changchun 130062, China.
  • 9 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 10 Guangzhou Medical University, Guangzhou 511436, China.
  • 11 Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 12 Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China.
  • 13 State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 14 Forevergen Biosciences Center, Guangzhou 510000, China.
  • 15 Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 16 Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China.
  • 17 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.
  • 18 Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
  • 19 Hannover Medical School, Institute of Experimental Hematology, Hannover 30625, Germany.
  • 20 Division of Hematology and Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 21 Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 22 Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg DK1870C, Denmark.
  • 23 Departments of Pediatrics and Child Health and Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, Canada.
  • 24 Department of Bone and Skeletal Research, Institute of Musculoskeletal Medicine, Medical Faculty of the University of Münster, Münster D-48149, Germany.
  • 25 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08003, Spain.
  • 26 Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 27 Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 28 Laboratory of Metabolism and Epigenetics, Institutes of Biomedical Sciences, Medical College of Fudan University, Shanghai 200032, China.
  • 29 Institute of Stem Cells and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
PMID: 32832621 DOI: 10.1126/sciadv.aba1593
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 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-80013
    99.84%, CDK7 Inhibitor
    CDK