Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

• Nicola Festuccia ^[2] ; Florian Halbritter ^[1] ; Andrea Corsinotti ^[3] ; Alessia Gagliardi ^[4] ; Douglas Colby ^[1] ; Simon R Tomlinson ^[1] ; Ian Chambers ^[1]
  1. [1] MRC Centre for Regenerative Medicine

     MRC Centre for Regenerative Medicine

     Reino Unido

     
  2. [2] 1 MRC Centre for Regenerative Medicine Institute for Stem Cell Research School of Biological Sciences University of Edinburgh Edinburgh UK; 3Present address: MRC London Institute of Medical Sciences Institute of Clinical Sciences Faculty of Medicine Imperial College London London UK
  3. [3] 1 MRC Centre for Regenerative Medicine Institute for Stem Cell Research School of Biological Sciences University of Edinburgh Edinburgh UK; 2 Department of Anatomy and Embryology Faculty of Medicine University of Tsukuba Ibaraki Japan
  4. [4] 1 MRC Centre for Regenerative Medicine Institute for Stem Cell Research School of Biological Sciences University of Edinburgh Edinburgh UK; 5Present address: Canada's Michael Smith Genome Sciences Centre BC Cancer Vancouver BC Canada

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 21, 2018, pág. 3
• Idioma: inglés
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  • Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Esrrbnegative ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrbpositive cells. Class I elements lose NANOG and OCT4 binding in Esrrbnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.