Premium
Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
Author(s) -
Festuccia Nicola,
Halbritter Florian,
Corsinotti Andrea,
Gagliardi Alessia,
Colby Douglas,
Tomlinson Simon R,
Chambers Ian
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695476
Subject(s) - regenerative medicine , library science , stem cell , biology , computer science , genetics
Self‐renewal of embryonic stem cells ( ESC s) 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 ( TF s), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESC s with distinct TF expression levels from LIF /FCS cultures to uncover early events during commitment from naïve pluripotency. ESC s carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanog low cells. Independent Esrrb reporter lines demonstrate that Esrrb negative ESC s cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. Ch IP ‐Seq identifies different regulatory element classes that bind both OCT 4 and NANOG in Esrrb positive cells. Class I elements lose NANOG and OCT 4 binding in Esrrb negative ESC s and associate with genes expressed preferentially in naïve ESC s. In contrast, Class II elements retain OCT 4 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.