Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the developing human placenta

• DOI: 10.1073/pnas.2002630117
• Publication Date: 2020-06-02T00:29:16Z
• Authors: Gudrun Meinhardt; Sandra Haider; Victoria Kunihs; Leila Saleh; Jürgen Pollheimer; Christian Fiala; Szabolcs Hetey; Zsofia Feher; Andras Szilagyi; Nandor Gabor Than; Martin Knöfler
• Keywords: Trophoblast; Cytotrophoblast; Syncytiotrophoblasts; Placentation

Various pregnancy complications, such as severe forms of preeclampsia or intrauterine growth restriction, are thought to arise from failures in the differentiation human placental trophoblasts. Progenitors latter either develop into invasive extravillous trophoblasts, remodeling uterine vasculature, fuse multinuclear syncytiotrophoblasts transporting oxygen and nutrients growing fetus. However, key regulatory factors controlling trophoblast self-renewal have been poorly elucidated. Using primary cells, three-dimensional organoids, CRISPR-Cas9 genome-edited JEG-3 clones, we herein show that YAP, transcriptional coactivator Hippo signaling pathway, promotes maintenance cytotrophoblast progenitors by different genomic mechanisms. Genetic chemical manipulation YAP these cellular models revealed it stimulates proliferation expression cell cycle regulators stemness-associated genes, but inhibits fusion production syncytiotrophoblast (STB)-specific proteins, hCG GDF15. Genome-wide comparisons villous cytotrophoblasts overexpressing constitutively active YAP-5SA with KO cells syncytializing trophoblasts common target genes involved stemness differentiation. ChIP-qPCR unraveled overexpression increased binding YAP–TEAD4 complexes promoters proliferation-associated CCNA CDK6 . Moreover, repressive containing histone methyltransferase EZH2 were detected regions STB-specific CGB5 CGB7 genes. In summary, plays a pivotal role epithelium. Besides activating factors, also directly represses promoting fusion.