DDX5-deficiency affects cell fate decisions by regulating lineage specific genes and polycomb repressive complexes. Mus musculus

RNA-binding proteins (RBPs) are involved in a wide variety of regulatory pathways in mammalian cells. Here, we report that the DEAD-box RBP DDX5 (also known as p68) inhibits induced pluripotency by negatively regulating the expression and function of a non-canonical polycomb complex 1 (PRC1) subunit, RYBP, by modulating microRNA-125b processing. DDX5 loss-of-function, both during reprogramming and the somatic to pluripotent transition, and also in the differentiation of mouse embryonic stem cells, results in the suppression of lineage-specific genes via an RYBP-dependent ubiquitination of histone H2A at K119 (H2AK119ub1). RYBP functions as both transcriptional repressor through PRC1 but also as an activator through its interaction with OCT4 during reprogramming. Diminished DDX5 also potentiates RYBP-mediated recruitment of OCT4 to the promoter of the pluripotency activation gene Kdm2b. These data show that DDX5 down-regulation stimulates silencing of lineage-specific genes by RYBP-PRC1 in the early phase of reprogramming and activation of the pluripotency gene network by RYBP-OCT4 in the later phase of reprogramming. Overall design: Examination of RYBP and H2AK119ub in WT or DDX5-/- ESCs using ChIP-seq