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JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process

BACKGROUND: The generation of induced pluripotent stem cells (iPSCs) has underdefined mechanisms. In addition, leukemia inhibitory factor (LIF) activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is the master regulator for naïve-state pluripotency achieveme...

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Autores principales: Wang, Ling, Jiang, Zongliang, Huang, Delun, Duan, Jingyue, Huang, Chang, Sullivan, Shannon, Vali, Kaneha, Yin, Yexuan, Zhang, Ming, Wegrzyn, Jill, Tian, Xiuchun ( Cindy), Tang, Young
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840728/
https://www.ncbi.nlm.nih.gov/pubmed/29510661
http://dx.doi.org/10.1186/s12864-018-4507-2
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author Wang, Ling
Jiang, Zongliang
Huang, Delun
Duan, Jingyue
Huang, Chang
Sullivan, Shannon
Vali, Kaneha
Yin, Yexuan
Zhang, Ming
Wegrzyn, Jill
Tian, Xiuchun ( Cindy)
Tang, Young
author_facet Wang, Ling
Jiang, Zongliang
Huang, Delun
Duan, Jingyue
Huang, Chang
Sullivan, Shannon
Vali, Kaneha
Yin, Yexuan
Zhang, Ming
Wegrzyn, Jill
Tian, Xiuchun ( Cindy)
Tang, Young
author_sort Wang, Ling
collection PubMed
description BACKGROUND: The generation of induced pluripotent stem cells (iPSCs) has underdefined mechanisms. In addition, leukemia inhibitory factor (LIF) activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is the master regulator for naïve-state pluripotency achievement and maintenance. However, the regulatory process to attain naïve pluripotent iPSCs is not well understood. RESULTS: We performed transcriptome analysis to dissect the genomic expression during mouse iPSC induction, with or without blocking the JAK/STAT3 activity. We describe JAK/STAT3 signaling-specific biological events such as gametogenesis, meiotic/mitotic cell cycle, and DNA repair, and JAK/STAT3-dependent expression of key transcription factors such as the naïve pluripotency-specific genes, developmental pluripotency associated (Dppa) family, along with histone modifiers and non-coding RNAs in reprogramming. We discover that JAK/STAT3 activity does not affect early phase mesenchymal to epithelial transition (MET) but is necessary for proper imprinting of the Dlk1-Dio3 region, an essential event for pluripotency achievement at late-reprogramming stage. This correlates with the JAK/STAT3-dependent stimulation of Dppa3 and Polycomb repressive complex 2 (PRC2) genes. We further demonstrate that JAK/STAT3 activity is essential for DNA demethylation of pluripotent loci including Oct4, Nanog, and the Dlk1-Dio3 regions. These findings correlate well with the previously identified STAT3 direct targets. We further propose a model of pluripotency achievement regulated by JAK/STAT3 signaling during the reprogramming process. CONCLUSIONS: Our study illustrates novel insights for JAK/STAT3 promoted pluripotency establishment, which are valuable for further improving the naïve-pluripotent iPSC generation across different species including humans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-018-4507-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-58407282018-03-09 JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process Wang, Ling Jiang, Zongliang Huang, Delun Duan, Jingyue Huang, Chang Sullivan, Shannon Vali, Kaneha Yin, Yexuan Zhang, Ming Wegrzyn, Jill Tian, Xiuchun ( Cindy) Tang, Young BMC Genomics Research Article BACKGROUND: The generation of induced pluripotent stem cells (iPSCs) has underdefined mechanisms. In addition, leukemia inhibitory factor (LIF) activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is the master regulator for naïve-state pluripotency achievement and maintenance. However, the regulatory process to attain naïve pluripotent iPSCs is not well understood. RESULTS: We performed transcriptome analysis to dissect the genomic expression during mouse iPSC induction, with or without blocking the JAK/STAT3 activity. We describe JAK/STAT3 signaling-specific biological events such as gametogenesis, meiotic/mitotic cell cycle, and DNA repair, and JAK/STAT3-dependent expression of key transcription factors such as the naïve pluripotency-specific genes, developmental pluripotency associated (Dppa) family, along with histone modifiers and non-coding RNAs in reprogramming. We discover that JAK/STAT3 activity does not affect early phase mesenchymal to epithelial transition (MET) but is necessary for proper imprinting of the Dlk1-Dio3 region, an essential event for pluripotency achievement at late-reprogramming stage. This correlates with the JAK/STAT3-dependent stimulation of Dppa3 and Polycomb repressive complex 2 (PRC2) genes. We further demonstrate that JAK/STAT3 activity is essential for DNA demethylation of pluripotent loci including Oct4, Nanog, and the Dlk1-Dio3 regions. These findings correlate well with the previously identified STAT3 direct targets. We further propose a model of pluripotency achievement regulated by JAK/STAT3 signaling during the reprogramming process. CONCLUSIONS: Our study illustrates novel insights for JAK/STAT3 promoted pluripotency establishment, which are valuable for further improving the naïve-pluripotent iPSC generation across different species including humans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-018-4507-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-06 /pmc/articles/PMC5840728/ /pubmed/29510661 http://dx.doi.org/10.1186/s12864-018-4507-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Wang, Ling
Jiang, Zongliang
Huang, Delun
Duan, Jingyue
Huang, Chang
Sullivan, Shannon
Vali, Kaneha
Yin, Yexuan
Zhang, Ming
Wegrzyn, Jill
Tian, Xiuchun ( Cindy)
Tang, Young
JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process
title JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process
title_full JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process
title_fullStr JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process
title_full_unstemmed JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process
title_short JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process
title_sort jak/stat3 regulated global gene expression dynamics during late-stage reprogramming process
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840728/
https://www.ncbi.nlm.nih.gov/pubmed/29510661
http://dx.doi.org/10.1186/s12864-018-4507-2
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