A genome-wide CRISPR-Cas9 screen in human trophoblast stem cells

Our study describing a genome-wide CRISPR-Cas9 knockout screen for essential and growth-restricting genes in human trophoblast stem cells (hTSCs) was published in Nature Communications today. By cross-referencing our results to those from similar genetic screens performed in other cell types, as well as gene expression data from early human embryos, we define hTSC-specific and -enriched regulators. These include both well-established and previously uncharacterized trophoblast regulators. Integrated analysis of chromatin accessibility, gene expression, and genome-wide location data reveals that the hTSC-specific essential transcription factor TEAD1 regulates the expression of many trophoblast regulators in hTSCs. In the absence of TEAD1, hTSCs fail to complete faithful differentiation into extravillous trophoblast (EVT) cells and instead show a bias towards syncytiotrophoblast (STB) differentiation. Overall, our study provides a valuable resource for dissecting the molecular regulation of human placental development and pregnancy-related diseases. Congratulations to Chen Dong, who spearheaded this project in collaboration with Shuhua Fu in Bo Zhang’s lab at WashU, and all other contributors!

Paper on stem-cell-derived trophoblast organoids

Our paper on stem-cell-derived trophoblast organoids (SC-TOs) was published in Cell Stem Cell today. In this work we describe a methodology for deriving self-renewing 3D trophoblast organoids from naive human pluripotent stem cells (hPSCs). Using single cell transcriptome analysis, we demonstrate that these organoids contain diverse trophoblast progenitor and specialized cell types that closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures also model placental X inactivation dynamics and selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus). Big congrats to all members of the team, especially Rowan Karvas, and our collaborators Indira Mysorekar, Sabine Dietmann, Jacco Boon, and Liang Ma!

OCT4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human

Our paper mapping the interactomes of the master transcription factor OCT4 in naive and primed human embryonic stem cells (hESCs) was published today in Nature Communications. We report that OCT4 cooperates with cell state-specific chromatin modifiers in naive and primed hESCs to promote an open chromatin architecture at blastocyst-associated and pan-ectodermal genes, respectively. This work was a collaboration between our team at WashU, Xin Huang and Jianlong Wang at Columbia University, Cigall Kadoch at the Dana-Farber Cancer Institute, and Rudolf Jaenisch at the Whitehead Institute. The WashU team was spearheaded by Kyoung-mi Park in the Theunissen lab in collaboration with the labs of Bo Zhang, Sabine Dietmann, and Ting Wang.

Probing the signaling requirements for naive human pluripotency

Our paper investigating the signaling requirements for naive human pluripotency by high-throughput chemical screening was published today in Cell Reports. We report that naive hESCs can be maintained by blocking distinct nodes in the FGF signaling pathway and that dual MEK/ERK inhibition promotes efficient primed-to-naive resetting in combination with Activin A. This study was a collaboration between Washington University School of Medicine, the Novartis Institutes for Biomedical Research, and the Whitehead Institute for Biomedical Research