YAP1 regulates the self-organized fate patterning of hESC-derived gastruloids

Eleonora Stronati; Servando Giraldez; Ling Huang; Elizabeth Abraham; Gillian R. McGuire; Hui Ting Hsu; Kathy A. Jones; Conchi Estarás

doi:10.1016/j.stemcr.2021.12.012

YAP1 regulates the self-organized fate patterning of hESC-derived gastruloids

Eleonora Stronati, Servando Giraldez, Ling Huang, Elizabeth Abraham, Gillian R. McGuire, Hui Ting Hsu, Kathy A. Jones, Conchi Estarás

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

The gastrulation process relies on complex interactions between developmental signaling pathways that are not completely understood. Here, we interrogated the contribution of the Hippo signaling effector YAP1 to the formation of the three germ layers by analyzing human embryonic stem cell (hESC)-derived 2D-micropatterned gastruloids. YAP1 knockout gastruloids display a reduced ectoderm layer and enlarged mesoderm and endoderm layers compared with wild type. Furthermore, our epigenome and transcriptome analysis revealed that YAP1 attenuates Nodal signaling by directly repressing the chromatin accessibility and transcription of key genes in the Nodal pathway, including the NODAL and FOXH1 genes. Hence, in the absence of YAP1, hyperactive Nodal signaling retains SMAD2/3 in the nuclei, impeding ectoderm differentiation of hESCs. Thus, our work revealed that YAP1 is a master regulator of Nodal signaling, essential for instructing germ layer fate patterning in human gastruloids.

Original language	English
Pages (from-to)	211-220
Number of pages	10
Journal	Stem Cell Reports
Volume	17
Issue number	2
DOIs	https://doi.org/10.1016/j.stemcr.2021.12.012
State	Published - Feb 8 2022

Keywords

Bone Morphogenetic Protein 4/pharmacology
Cell Differentiation
Chromatin Assembly and Disassembly
Ectoderm/cytology
Forkhead Transcription Factors/genetics
Human Embryonic Stem Cells/cytology
Humans
Microscopy, Fluorescence
Models, Biological
Nodal Protein/antagonists & inhibitors
Signal Transduction
Smad2 Protein/metabolism
Smad3 Protein/metabolism
Stomach/cytology
YAP-Signaling Proteins/deficiency

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10.1016/j.stemcr.2021.12.012

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title = "YAP1 regulates the self-organized fate patterning of hESC-derived gastruloids",

abstract = "The gastrulation process relies on complex interactions between developmental signaling pathways that are not completely understood. Here, we interrogated the contribution of the Hippo signaling effector YAP1 to the formation of the three germ layers by analyzing human embryonic stem cell (hESC)-derived 2D-micropatterned gastruloids. YAP1 knockout gastruloids display a reduced ectoderm layer and enlarged mesoderm and endoderm layers compared with wild type. Furthermore, our epigenome and transcriptome analysis revealed that YAP1 attenuates Nodal signaling by directly repressing the chromatin accessibility and transcription of key genes in the Nodal pathway, including the NODAL and FOXH1 genes. Hence, in the absence of YAP1, hyperactive Nodal signaling retains SMAD2/3 in the nuclei, impeding ectoderm differentiation of hESCs. Thus, our work revealed that YAP1 is a master regulator of Nodal signaling, essential for instructing germ layer fate patterning in human gastruloids.",

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author = "Eleonora Stronati and Servando Giraldez and Ling Huang and Elizabeth Abraham and McGuire, {Gillian R.} and Hsu, {Hui Ting} and Jones, {Kathy A.} and Conchi Estar{\'a}s",

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AU - Giraldez, Servando

AU - Huang, Ling

AU - Abraham, Elizabeth

AU - McGuire, Gillian R.

AU - Hsu, Hui Ting

AU - Jones, Kathy A.

AU - Estarás, Conchi

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AB - The gastrulation process relies on complex interactions between developmental signaling pathways that are not completely understood. Here, we interrogated the contribution of the Hippo signaling effector YAP1 to the formation of the three germ layers by analyzing human embryonic stem cell (hESC)-derived 2D-micropatterned gastruloids. YAP1 knockout gastruloids display a reduced ectoderm layer and enlarged mesoderm and endoderm layers compared with wild type. Furthermore, our epigenome and transcriptome analysis revealed that YAP1 attenuates Nodal signaling by directly repressing the chromatin accessibility and transcription of key genes in the Nodal pathway, including the NODAL and FOXH1 genes. Hence, in the absence of YAP1, hyperactive Nodal signaling retains SMAD2/3 in the nuclei, impeding ectoderm differentiation of hESCs. Thus, our work revealed that YAP1 is a master regulator of Nodal signaling, essential for instructing germ layer fate patterning in human gastruloids.

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KW - Stomach/cytology

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YAP1 regulates the self-organized fate patterning of hESC-derived gastruloids

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Keywords

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YAP1 molecule essential to development of gastruloids using embryonic stem cells; findings may have implications for cancer

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YAP1 regulates the self-organized fate patterning of hESC-derived gastruloids

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YAP1 molecule essential to development of gastruloids using embryonic stem cells; findings may have implications for cancer

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