YAP1 and QSER1 are Key Modulators of Embryonic Signaling Pathways in the Mammalian Epiblast [ChIP-seq]

The Hippo:YAP1 signaling pathway was long considered a master regulator of organ growth. However, recent evidence has challenged this view, showing that the loss of YAP1 does not prevent several organs from reaching their normal size. Hence, resolving the functions of YAP1 in the embryo has become a central question in the field. To shed light into this, we analyzed YAP1’s role in regulating pluripotency of the mammalian epiblast, using scRNAseq approaches. Conditional deletion of Yap1 in the mouse epiblast (Sox2-Cre) altered the expression of signaling and differentiation genes, including Nodal, Wnt3, Fgf8, and Nanog, without impairing cell proliferation. Instead, Yap1 loss led to hyperactivation of Nodal signaling and enhanced differentiation of the epiblast toward mesodermal fate. Furthermore, an unbiased screening in human pluripotent stem cells revealed that YAP1 transcriptionally cooperates with QSER1 protein, to regulate multiple WNT and NODAL signaling genes. Mechanistically, QSER1 represses lineage enhancers of signaling genes by counteracting RNA Polymerase II recruitment on YAP1-targets. Accordingly, QSER1 depletion, similar to YAP1, leads to hyperactive Nodal signaling in human 2D-gastruloids. Overall, our findings not only advance our understanding of YAP1’s role in early development but also open new avenues for exploring how the interplay with QSER1 could influence additional developmental processes.