SRP125685 PRJNA419920 GSE107377 PCGF5 is required for neural differentiation of embryonic stem cells [ChIP-seq] Polycomb-group proteins are key regulators of the transcriptional programs that maintain stem cell identity and dictate lineage specification. Polycomb repressor complex 1 (PRC1) contains the E3 ligases RING1A/B, which monoubiquitinate lysine 119 at histone H2A (H2AK119ub1) to regulate gene expression. PRC1 has been sub-classified into six major complexes based on the presence of a PCGF subunit. Here, we find that Pcgf5, one of six PCGF paralogs, is an important requirement in the differentiation of mouse embryonic stem cells (mESCs) towards a neural cell fate. Although PCGF5 is not required for mESC self-renewal, its loss blocks mESC neural differentiation by activating the SMAD2/TGF-ß signaling pathway. Inhibition of SMAD2/TGF-ß signaling or rescue by overexpression of Pcgf5 can restore the capability of mESCs to differentiate towards a neural cell fate. PCGF5 works by stimulating RING1B-dependent H2AK119ub1 both in vitro and in vivo, leading to the suppression of TGF-ß signaling genes. PCGF5 loss-of-function prevents the reduction of H2AK119ub1 and H3K27me3 around neural specific genes and keeps them repressed. Our results showed that PCGF5 might function as both a repressor for SMAD2/TGF-ß signaling pathway and a facilitator for neural differentiation. Together, our findings reveal a critical context-specific function for PCGF5 in directing PRC1 to control cell fate. Overall design: H2AK119ub1 and H3K27me3 ChIP-seq with a drosophila chromatin spike-in were performed in wild type, PCGF5-depleted mESCs and the differentiated NPCs at day 6 after neural differentiation of mESCs, respectively. PCGF5 ChIP-seq was performed in NPCs at day 6 after neural differentiation of mESCs. GSE107377 pubmed 29765032