GSE168377
YAP1 Drives Lineage Specification and Patterning in hESC-derived Gastruloids
The gastrulation process is controlled by the interplay between morphogenetic signals from BMP, WNT and NODAL pathways. Increasing evidences support an emerging role of the Hippo-YAP signaling in the cell-fate decisions that guide lineage specification in mouse and human Embryonic Stem Cells (hESCs).  However, the contribution of YAP to the process of gastrulation in hESCs remains unknown. Here, we show that YAP1 regulates the specification, size and patterning of the three-germ layers.  Using hESC-derived 2D-micropatterned gastruloids and directed differentiation approaches we show that YAP maintains a semi-active NODAL signaling during gastrulation essential to regulate the exit of pluripotency. In absence of YAP1, a hyperactive NODAL signaling retains SMAD2.3 in the nuclei, impeding the exit of pluripotency and the acquisition of the ectodermal gene program. Accordingly, the inhibition of NODAL signaling is sufficient to rescue the gastrulation-defective phenotype of the YAP1 KO hESCs. Our work revealed that Hippo-YAP1 signaling is an important component of the developmental network that coordinate hESC pluripotency and gastrulation. Overall design: We used a directed differentiation protocol (StemCell Technologies #05230) to induce human embryonic stem cells  (hESC) differentiation towards ectoderm, mesoderm and endoderm lineages in WT and YAP1 KO and performed gene expression profiling using RNA-Seq. We also included controls of undifferentiated hESC. In addition, single-nuclei ATAC-seq  (snATAC) was used to examine the genome-wide chromatin accessibility profile in WT and YAP1 KO hESCs.