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Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers
Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of diff...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367178/ https://www.ncbi.nlm.nih.gov/pubmed/32510157 http://dx.doi.org/10.1093/nar/gkaa482 |
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author | Sun, Xiang Ren, Zhijun Cun, Yixian Zhao, Cai Huang, Xianglin Zhou, Jiajian Hu, Rong Su, Xiaoxi Ji, Lu Li, Peng Mak, King Lun Kingston Gao, Feng Yang, Yi Xu, He Ding, Junjun Cao, Nan Li, Shuo Zhang, Wensheng Lan, Ping Sun, Hao Wang, Jinkai Yuan, Ping |
author_facet | Sun, Xiang Ren, Zhijun Cun, Yixian Zhao, Cai Huang, Xianglin Zhou, Jiajian Hu, Rong Su, Xiaoxi Ji, Lu Li, Peng Mak, King Lun Kingston Gao, Feng Yang, Yi Xu, He Ding, Junjun Cao, Nan Li, Shuo Zhang, Wensheng Lan, Ping Sun, Hao Wang, Jinkai Yuan, Ping |
author_sort | Sun, Xiang |
collection | PubMed |
description | Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of differentiation into mesendoderm lineage. To further uncover the underlying regulatory mechanisms, we performed a series of ChIP-seq experiments with antibodies against YAP, ESC master transcription factors and some characterized histone modification markers as well as RNA-seq assays using wild type and Mst KO samples at ES and day 4 embryoid body stage respectively. We demonstrate that YAP is preferentially co-localized with super-enhancer (SE) markers such as Nanog, Sox2, Oct4 and H3K27ac in ESCs. The hyper-activation of nuclear YAP in Mst KO ESCs facilitates the binding of Nanog, Sox2 and Oct4 as well as H3K27ac modification at the loci where YAP binds. Moreover, Mst depletion results in novel SE formation and enhanced liquid-liquid phase-separated Med1 condensates on lineage associated genes, leading to the upregulation of these genes and the distortion of ESC differentiation. Our study reveals a novel mechanism on how Hippo-YAP signaling pathway dictates ESC lineage differentiation. |
format | Online Article Text |
id | pubmed-7367178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-73671782020-07-22 Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers Sun, Xiang Ren, Zhijun Cun, Yixian Zhao, Cai Huang, Xianglin Zhou, Jiajian Hu, Rong Su, Xiaoxi Ji, Lu Li, Peng Mak, King Lun Kingston Gao, Feng Yang, Yi Xu, He Ding, Junjun Cao, Nan Li, Shuo Zhang, Wensheng Lan, Ping Sun, Hao Wang, Jinkai Yuan, Ping Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of differentiation into mesendoderm lineage. To further uncover the underlying regulatory mechanisms, we performed a series of ChIP-seq experiments with antibodies against YAP, ESC master transcription factors and some characterized histone modification markers as well as RNA-seq assays using wild type and Mst KO samples at ES and day 4 embryoid body stage respectively. We demonstrate that YAP is preferentially co-localized with super-enhancer (SE) markers such as Nanog, Sox2, Oct4 and H3K27ac in ESCs. The hyper-activation of nuclear YAP in Mst KO ESCs facilitates the binding of Nanog, Sox2 and Oct4 as well as H3K27ac modification at the loci where YAP binds. Moreover, Mst depletion results in novel SE formation and enhanced liquid-liquid phase-separated Med1 condensates on lineage associated genes, leading to the upregulation of these genes and the distortion of ESC differentiation. Our study reveals a novel mechanism on how Hippo-YAP signaling pathway dictates ESC lineage differentiation. Oxford University Press 2020-07-27 2020-06-08 /pmc/articles/PMC7367178/ /pubmed/32510157 http://dx.doi.org/10.1093/nar/gkaa482 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Gene regulation, Chromatin and Epigenetics Sun, Xiang Ren, Zhijun Cun, Yixian Zhao, Cai Huang, Xianglin Zhou, Jiajian Hu, Rong Su, Xiaoxi Ji, Lu Li, Peng Mak, King Lun Kingston Gao, Feng Yang, Yi Xu, He Ding, Junjun Cao, Nan Li, Shuo Zhang, Wensheng Lan, Ping Sun, Hao Wang, Jinkai Yuan, Ping Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers |
title | Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers |
title_full | Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers |
title_fullStr | Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers |
title_full_unstemmed | Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers |
title_short | Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers |
title_sort | hippo-yap signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367178/ https://www.ncbi.nlm.nih.gov/pubmed/32510157 http://dx.doi.org/10.1093/nar/gkaa482 |
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