Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
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
_version_ 1783560368910499840
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
work_keys_str_mv AT sunxiang hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT renzhijun hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT cunyixian hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT zhaocai hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT huangxianglin hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT zhoujiajian hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT hurong hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT suxiaoxi hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT jilu hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT lipeng hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT makkinglunkingston hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT gaofeng hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT yangyi hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT xuhe hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT dingjunjun hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT caonan hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT lishuo hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT zhangwensheng hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT lanping hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT sunhao hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT wangjinkai hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers
AT yuanping hippoyapsignalingcontrolslineagedifferentiationofmouseembryonicstemcellsthroughmodulatingtheformationofsuperenhancers