Abstract
SummaryThe gene regulatory network (GRN) of naive mouse embryonic stem cells (ESCs) 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 signaling, ETV5 switches activity from supporting self-renewal and undergoes genome relocation linked to commissioning of enhancers activated in formative epiblast. Independent upregulation of RBPJ prevents re-expression of potent naive factors, TBX3 and NANOG, to secure exit from the naive state. Triple deletion of Etv5, Rbpj, and Tcf3 disables ESCs, 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.
Highlights
Mouse embryonic stem cells (ESCs) are in vitro cell lines that retain a high degree of molecular and functional correspondence with the naive pluripotent epiblast of the pre-implantation embryo (Boroviak et al, 2014; Bradley et al, 1984; Evans and Kaufman, 1981; Martin, 1981)
Identification of ETV5 as a Candidate Driver of Progression from Naive to Formative Pluripotency To identify factors that may mediate the effect of ERK pathway inhibition in driving pluripotency network transition, we inspected results from loss-of-function screens
We noted that Etv5 is the most recurrent hit after Tcf3 in a random mutagenesis screen (Leeb et al, 2014) and is a highconfidence candidate from a genome-wide small interfering RNA screen (Yang et al, 2012)
Summary
Mouse embryonic stem cells (ESCs) are in vitro cell lines that retain a high degree of molecular and functional correspondence with the naive pluripotent epiblast of the pre-implantation embryo (Boroviak et al, 2014; Bradley et al, 1984; Evans and Kaufman, 1981; Martin, 1981). They provide a rich resource for studying mechanisms underlying developmental decisions and transitions. The naıve-to-formative conversion in a simple and well-defined culture environment simulates events in the peri-implantation mouse embryo (Kalkan et al, 2017) and provides a sensitized platform for identifying factors and mechanisms that mediate change in cell identity (Buecker et al, 2014; Kalkan and Smith, 2014)
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