DDX18 safeguards rDNA epigenetic landscape by counteracting PRC2 and maintains ESC identity

Here we have RNA binding protein DDX18 connecting rRNA transcription to early embryo development and embryonic stem cell (ESC) identity maintenance. DDX18 mutant embryos suffer lethality during preimplantation development. DDX18 depletion impairs ESC self-renewal and pluripotency, which phenotype-copies RNA polymerase I (RNAPI) inhibition. Mechanistically, DDX18 is recruited to rDNA by RNAPI transcription machinery and senses rRNA transcription by binding to pre-rRNA. In nucleolus, DDX18 surrounds DFC ring and interacts with PRC2. In the presence of transcribed pre-rRNA, DDX18 interaction with PRC2 makes EZH2 unstably binding to the other components of PRC2, thereby preventing PRC2 engagement and counteracting H3K27me3 mediated silencing at rDNA chromatin. Together, our study shows that DDX18 plays important roles in safeguarding ESCs identity through regulating epigenetic states of rDNA locus and maintaining euchromatin structure in nucleolus.