Taking the RISC of exiting naïve pluripotency

ESCs are characterized by an open chromatin structure and global hyper-transcription,
with tight control of transcriptional ‘leakage’ 3], 4]. While ESCs can be maintained in the absence of chromatin repressors, primed EpiSCs
are highly sensitive to the loss of these regulators 5], although the transcriptional level of these proteins is not greatly affected by
the induction of differentiation. Interestingly, Pandolfini and colleagues 1] found that chromatin regulators and repressors are among the main targets of RISC-mediated
translational inhibition in naïve ESCs 1]. In particular, they showed how the protein abundance of members of the DNA methyltransferase
(DNMT), histone lysine demethylase (KDM), and SWItch/Sucrose Non-Fermentable nucleosome
remodeling complex (SWI/SNF) families of epigenetic regulators are tightly regulated
during the exit from ground-state pluripotency. Through the integration of RNAseq,
polysome profiling, and the immunoprecipitation of Argonaute (Ago; the main RNA-binding
RISC component), the authors elegantly show how RISC posttranscriptionally modulates
the translation levels of these epigenetic regulators.

Once differentiation starts, RISC-loaded mRNAs of DNMT, KDM, and SWI/SNF proteins
are coordinately released for translation; the resultant increase in their protein
abundance shuts down the naive pluripotency transcriptional network, allowing cell
differentiation (Fig. 1). Studies of the functional inhibition of DNMT, KDM, and SWI/SNF during the ESC-to-ELA
transition showed that the activity of these chromatin regulators during priming is
necessary for down-regulating both the naïve marker Nanog and markers of pluripotency
(Klf4, Rex1, and Dax1) and for up-regulating priming markers 1]. Together, these results clearly show that the induction of chromatin modifiers is
required for the naïve-to-primed transition.