Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States; Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, United States
Bum-Kyu Lee
Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States; Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, United States
Andy C Yu
Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
Mijeong Kim
Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States; Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, United States
Aparna V Kambhampati
Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
Shannon M Dupont
Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
Davide Seruggia
Division of Hematology/Oncology, Boston Children’s Hospital, Boston, United States; Harvard Stem Cell Institute, Harvard Medical School, Boston, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Boston, United States
Byoung U Ryu
Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
Stuart H Orkin
Division of Hematology/Oncology, Boston Children’s Hospital, Boston, United States; Howard Hughes Medical Institute, Boston, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Boston, United States; Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States; Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, United States
Approximately, 30% of embryonic stem cells (ESCs) die after exiting self-renewal, but regulators of this process are not well known. Yap1 is a Hippo pathway transcriptional effector that plays numerous roles in development and cancer. However, its functions in ESC differentiation remain poorly characterized. We first reveal that ESCs lacking Yap1 experience massive cell death upon the exit from self-renewal. We subsequently show that Yap1 contextually protects differentiating, but not self-renewing, ESC from hyperactivation of the apoptotic cascade. Mechanistically, Yap1 strongly activates anti-apoptotic genes via cis-regulatory elements while mildly suppressing pro-apoptotic genes, which moderates the level of mitochondrial priming that occurs during differentiation. Individually modulating the expression of single apoptosis-related genes targeted by Yap1 is sufficient to augment or hinder survival during differentiation. Our demonstration of the context-dependent pro-survival functions of Yap1 during ESC differentiation contributes to our understanding of the balance between survival and death during cell fate changes.
