Fig. 8. Working model for 2i and Cdk8/19i -mediated mechanisms involved in the stabilization of naïve pluripotency.

2i-dependent inhibition of Mek/Erk prevents phosphorylation of Erf and Cic, stabilizing both factors in the nucleus. These transcriptional effectors might participate in the activation of genes involved in naïve pluripotency whereas they repress factors involved in primed/formative states. Cdk8/19i affects the phosphorylation of proteins involved in elongation and transcription machineries such as super elongation complex (SEC), RNA pol II (RNPII) and Mediator (MED). This might lead to rapid activation of genes controlled by super-enhancers. These genes include factors that stabilize the naïve state but also some factors from the primed/formative states which are also upregulated in response to Cdk8/19i. Upon activation of the naïve circuitry in 2i and Cdk8/19i, several events might support the enhanced mitochondrial OXPHOS capacity of these cells. Degradation of Lin28a might relieve target mRNAs from its repression effects and, among others, mitochondrial proteins become upregulated. The balance of autophagy and protein synthesis may sustain the translation of such mitochondrial components. In addition, re-wiring of mitochondrial sources for one carbon units may also sustain the translation of mitochondrial-encoded proteins. On the other hand, the availability of SAM levels (by NNMT upregulation) together with the impairment of DNA methylation (by Uhrf1 degradation) contribute to the hypomethylated DNA typical of 2i.