A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells

Chen Dong, Shuhua Fu, Rowan M. Karvas, Brian Chew, Laura A. Fischer, Xiaoyun Xing, Jessica K. Harrison, Pooja Popli, Ramakrishna Kommagani, Ting Wang, Bo Zhang () and Thorold W. Theunissen ()
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Chen Dong: Washington University School of Medicine
Shuhua Fu: Washington University School of Medicine
Rowan M. Karvas: Washington University School of Medicine
Brian Chew: Washington University School of Medicine
Laura A. Fischer: Washington University School of Medicine
Xiaoyun Xing: Washington University School of Medicine
Jessica K. Harrison: Washington University School of Medicine
Pooja Popli: Washington University School of Medicine
Ramakrishna Kommagani: Washington University School of Medicine
Ting Wang: Washington University School of Medicine
Bo Zhang: Washington University School of Medicine
Thorold W. Theunissen: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The recent derivation of human trophoblast stem cells (hTSCs) provides a scalable in vitro model system of human placental development, but the molecular regulators of hTSC identity have not been systematically explored thus far. Here, we utilize a genome-wide CRISPR-Cas9 knockout screen to comprehensively identify essential and growth-restricting genes in hTSCs. By cross-referencing our data 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, such as ARID3A, GATA2, and TEAD1 (essential), and GCM1, PTPN14, and TET2 (growth-restricting). Integrated analysis of chromatin accessibility, gene expression, and genome-wide location data reveals that the 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, thus indicating that this transcription factor safeguards the bipotent lineage potential of hTSCs. Overall, our study provides a valuable resource for dissecting the molecular regulation of human placental development and diseases.

Date: 2022
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DOI: 10.1038/s41467-022-30207-9

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