Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency.
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Authors
Kalkan, Tüzer
Diamanti, Evangelia
Middelkamp, Sjors
Lombard, Patrick
Publication Date
2019-05Journal Title
Cell stem cell
ISSN
1934-5909
Publisher
Cell Press
Volume
24
Issue
5
Pages
785-801.e7
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Kalkan, T., Borneloev, S., Mulas, C., Diamanti, E., Lohoff, T., Ralser, M., Middelkamp, S., et al. (2019). Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency.. Cell stem cell, 24 (5), 785-801.e7. https://doi.org/10.1016/j.stem.2019.03.017
Abstract
The gene regulatory network (GRN) of naïve mouse embryonic stem cells (ESC) must be
reconfigured to enable lineage commitment. TCF3 sanctions rewiring by suppressing
components of the ESC transcription factor circuitry. However, TCF3 depletion only delays,
and does not prevent, transition to formative pluripotency. Here we delineate additional
contributions of the ETS-family transcription factor ETV5 and the repressor RBPJ. In response
to ERK signalling, ETV5 switches activity from supporting self-renewal and undergoes
genome relocation linked to commissioning of enhancers activated in formative epiblast.
Independent up-regulation of RBPJ prevents re-expression of potent naïve factors, TBX3 and
NANOG, to secure exit from the naïve state. Triple deletion of Etv5, Rbpj and Tcf3 disables
Manuscript
ESC, such that they remain largely undifferentiated and locked in self-renewal even in the
presence of differentiation stimuli. Thus genetic elimination of three complementary drivers of
network transition stalls developmental progression, emulating environmental insulation by
small molecule inhibitors.
Keywords
Neurons, Cell Line, Pluripotent Stem Cells, Animals, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, DNA-Binding Proteins, T-Box Domain Proteins, Transcription Factors, RNA, Small Interfering, Cell Differentiation, Cell Lineage, Basic Helix-Loop-Helix Transcription Factors, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Gene Regulatory Networks, Gene Knockout Techniques, Cell Self Renewal, Nanog Homeobox Protein
Sponsorship
This research was funded by the Wellcome
Trust, the Biotechnology and Biological Sciences Research Council, European Commission
(contract no. 200720, EuroSyStem) and the Louis Jeantet Foundation. The Cambridge Stem
Cell Institute receives core support from the Wellcome Trust and the Medical Research
Council. AS is a Medical Research Council Professor.
Funder references
European Commission (200720)
Wellcome Trust (097922/Z/11/Z)
MRC (MR/P00072X/1)
BBSRC (BB/M004023/1)
Identifiers
External DOI: https://doi.org/10.1016/j.stem.2019.03.017
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291454
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/