Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.

A 30-node signed and directed network responsible for self-renewal and pluripotency of mouse embryonic stem cells (mESCs) was extracted from several ChIP-Seq and knockdown followed by expression prior studies. The underlying regulatory logic among network components was then learned using the initia...

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Autores principales:	Huilei Xu, Yen-Sin Ang, Ana Sevilla, Ihor R Lemischka, Avi Ma'ayan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e28f242edeaf49a8b2254fc2ceefa4b2
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spelling	oai:doaj.org-article:e28f242edeaf49a8b2254fc2ceefa4b22021-11-25T05:40:51ZConstruction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.1553-734X1553-735810.1371/journal.pcbi.1003777https://doaj.org/article/e28f242edeaf49a8b2254fc2ceefa4b22014-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25122140/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358A 30-node signed and directed network responsible for self-renewal and pluripotency of mouse embryonic stem cells (mESCs) was extracted from several ChIP-Seq and knockdown followed by expression prior studies. The underlying regulatory logic among network components was then learned using the initial network topology and single cell gene expression measurements from mESCs cultured in serum/LIF or serum-free 2i/LIF conditions. Comparing the learned network regulatory logic derived from cells cultured in serum/LIF vs. 2i/LIF revealed differential roles for Nanog, Oct4/Pou5f1, Sox2, Esrrb and Tcf3. Overall, gene expression in the serum/LIF condition was more variable than in the 2i/LIF but mostly consistent across the two conditions. Expression levels for most genes in single cells were bimodal across the entire population and this motivated a Boolean modeling approach. In silico predictions derived from removal of nodes from the Boolean dynamical model were validated with experimental single and combinatorial RNA interference (RNAi) knockdowns of selected network components. Quantitative post-RNAi expression level measurements of remaining network components showed good agreement with the in silico predictions. Computational removal of nodes from the Boolean network model was also used to predict lineage specification outcomes. In summary, data integration, modeling, and targeted experiments were used to improve our understanding of the regulatory topology that controls mESC fate decisions as well as to develop robust directed lineage specification protocols.Huilei XuYen-Sin AngAna SevillaIhor R LemischkaAvi Ma'ayanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 8, p e1003777 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Huilei Xu Yen-Sin Ang Ana Sevilla Ihor R Lemischka Avi Ma'ayan Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.
description	A 30-node signed and directed network responsible for self-renewal and pluripotency of mouse embryonic stem cells (mESCs) was extracted from several ChIP-Seq and knockdown followed by expression prior studies. The underlying regulatory logic among network components was then learned using the initial network topology and single cell gene expression measurements from mESCs cultured in serum/LIF or serum-free 2i/LIF conditions. Comparing the learned network regulatory logic derived from cells cultured in serum/LIF vs. 2i/LIF revealed differential roles for Nanog, Oct4/Pou5f1, Sox2, Esrrb and Tcf3. Overall, gene expression in the serum/LIF condition was more variable than in the 2i/LIF but mostly consistent across the two conditions. Expression levels for most genes in single cells were bimodal across the entire population and this motivated a Boolean modeling approach. In silico predictions derived from removal of nodes from the Boolean dynamical model were validated with experimental single and combinatorial RNA interference (RNAi) knockdowns of selected network components. Quantitative post-RNAi expression level measurements of remaining network components showed good agreement with the in silico predictions. Computational removal of nodes from the Boolean network model was also used to predict lineage specification outcomes. In summary, data integration, modeling, and targeted experiments were used to improve our understanding of the regulatory topology that controls mESC fate decisions as well as to develop robust directed lineage specification protocols.
format	article
author	Huilei Xu Yen-Sin Ang Ana Sevilla Ihor R Lemischka Avi Ma'ayan
author_facet	Huilei Xu Yen-Sin Ang Ana Sevilla Ihor R Lemischka Avi Ma'ayan
author_sort	Huilei Xu
title	Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.
title_short	Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.
title_full	Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.
title_fullStr	Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.
title_full_unstemmed	Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.
title_sort	construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/e28f242edeaf49a8b2254fc2ceefa4b2
work_keys_str_mv	AT huileixu constructionandvalidationofaregulatorynetworkforpluripotencyandselfrenewalofmouseembryonicstemcells AT yensinang constructionandvalidationofaregulatorynetworkforpluripotencyandselfrenewalofmouseembryonicstemcells AT anasevilla constructionandvalidationofaregulatorynetworkforpluripotencyandselfrenewalofmouseembryonicstemcells AT ihorrlemischka constructionandvalidationofaregulatorynetworkforpluripotencyandselfrenewalofmouseembryonicstemcells AT avimaayan constructionandvalidationofaregulatorynetworkforpluripotencyandselfrenewalofmouseembryonicstemcells
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Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells.

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