GATA3 Mediates a Fast, Irreversible Commitment to BMP4-Driven Differentiation in Human Embryonic Stem Cells.

Cell stem cell 2020 May 07

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During early development, extrinsic triggers prompt pluripotent cells to begin the process of differentiation. When and how human embryonic stem cells (hESCs) irreversibly commit to differentiation is a fundamental yet unanswered question. By combining single-cell imaging, genomic approaches, and mathematical modeling, we find that hESCs commit to exiting pluripotency unexpectedly early. We show that bone morphogenetic protein 4 (BMP4), an important differentiation trigger, induces a subset of early genes to mirror the sustained, bistable dynamics of upstream signaling. Induction of one of these genes, GATA3, drives differentiation in the absence of BMP4. Conversely, GATA3 knockout delays differentiation and prevents fast commitment to differentiation. We show that positive feedback at the level of the GATA3-BMP4 axis induces fast, irreversible commitment to differentiation. We propose that early commitment may be a feature of BMP-driven fate choices and that interlinked feedback is the molecular basis for an irreversible transition from pluripotency to differentiation. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Alexandra Gunne-Braden, Adrienne Sullivan, Borzo Gharibi, Rahuman S M Sheriff, Alok Maity, Yi-Fang Wang, Amelia Edwards, Ming Jiang, Michael Howell, Robert Goldstone, Roy Wollman, Philip East, Silvia D M Santos. GATA3 Mediates a Fast, Irreversible Commitment to BMP4-Driven Differentiation in Human Embryonic Stem Cells. Cell stem cell. 2020 May 07;26(5):693-706.e9