Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation
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 chara...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/40167 |
| _version_ | 1811227870416076800 |
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| author | Lucy LeBlanc Bum-Kyu Lee Andy C Yu Mijeong Kim Aparna V Kambhampati Shannon M Dupont Davide Seruggia Byoung U Ryu Stuart H Orkin Jonghwan Kim |
| author_facet | Lucy LeBlanc Bum-Kyu Lee Andy C Yu Mijeong Kim Aparna V Kambhampati Shannon M Dupont Davide Seruggia Byoung U Ryu Stuart H Orkin Jonghwan Kim |
| author_sort | Lucy LeBlanc |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:47:59Z |
| format | Article |
| id | doaj.art-c27f6bfa6c6c4174b6c51e74df547c46 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:47:59Z |
| publishDate | 2018-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c27f6bfa6c6c4174b6c51e74df547c462022-12-22T03:37:53ZengeLife Sciences Publications LtdeLife2050-084X2018-12-01710.7554/eLife.40167Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiationLucy LeBlanc0https://orcid.org/0000-0001-5945-3133Bum-Kyu Lee1Andy C Yu2Mijeong Kim3Aparna V Kambhampati4Shannon M Dupont5Davide Seruggia6Byoung U Ryu7Stuart H Orkin8Jonghwan Kim9https://orcid.org/0000-0002-9919-9843Department 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 StatesDepartment 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 StatesDepartment of Molecular Biosciences, The University of Texas at Austin, Austin, United StatesDepartment 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 StatesDepartment of Molecular Biosciences, The University of Texas at Austin, Austin, United StatesDepartment of Molecular Biosciences, The University of Texas at Austin, Austin, United StatesDivision 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 StatesDepartment of Molecular Biosciences, The University of Texas at Austin, Austin, United StatesDivision 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 StatesDepartment 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 StatesApproximately, 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.https://elifesciences.org/articles/40167Yap1apoptosisembryonic stem cellsdifferentiation |
| spellingShingle | Lucy LeBlanc Bum-Kyu Lee Andy C Yu Mijeong Kim Aparna V Kambhampati Shannon M Dupont Davide Seruggia Byoung U Ryu Stuart H Orkin Jonghwan Kim Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation eLife Yap1 apoptosis embryonic stem cells differentiation |
| title | Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation |
| title_full | Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation |
| title_fullStr | Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation |
| title_full_unstemmed | Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation |
| title_short | Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation |
| title_sort | yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation |
| topic | Yap1 apoptosis embryonic stem cells differentiation |
| url | https://elifesciences.org/articles/40167 |
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