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FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming

FOXH1 is a primitive-streak specifier and ACTIVIN co-effector that plays an important role in development, and positively regulates the generation of human induced pluripotent stem cells (iPSCs) from somatic cells by OCT4, SOX2, KLF4, and MYC (OSKM) transduction. However, the mechanism and upstream...

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Autores principales: Wang, Ling, Su, Yue, Huang, Chang, Yin, Yexuan, Zhu, Jiaqi, Knupp, Alec, Chu, Alexander, Tang, Young
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848184/
https://www.ncbi.nlm.nih.gov/pubmed/31712708
http://dx.doi.org/10.1038/s41598-019-52861-8
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author Wang, Ling
Su, Yue
Huang, Chang
Yin, Yexuan
Zhu, Jiaqi
Knupp, Alec
Chu, Alexander
Tang, Young
author_facet Wang, Ling
Su, Yue
Huang, Chang
Yin, Yexuan
Zhu, Jiaqi
Knupp, Alec
Chu, Alexander
Tang, Young
author_sort Wang, Ling
collection PubMed
description FOXH1 is a primitive-streak specifier and ACTIVIN co-effector that plays an important role in development, and positively regulates the generation of human induced pluripotent stem cells (iPSCs) from somatic cells by OCT4, SOX2, KLF4, and MYC (OSKM) transduction. However, the mechanism and upstream regulation for FOXH1 expression in reprogramming are unclear. We found FOXH1 expression plays a significant role to enhance epithelial marker and suppress mesenchymal gene expression in OSKM-mediated human cell reprogramming. Furthermore, NANOG and LIN28 (NL) co-stimulate FOXH1 expression, which correlates with the enhanced reprogramming efficiency by NL-factors. FOXH1 expression is also stimulated by a specific inhibitor for H3K79 methyltransferase DOT1L (iDOT1L) but not by inhibition of the canonical WNT signaling. We further show that blocking endogenous FOXH1 expression eliminates the enhanced reprogramming effect by NL and iDOT1L. However, overexpressing FOXH1 in NL plus iDOT1L condition results in significantly reduced TRA-1-60 positively expressed cells and decreases pluripotent marker expression in reprogramming. Our study elucidated an essential role for properly stimulated FOXH1 expression by NANOG, LIN28, and H3K79 demethylation for dramatic enhancement of reprograming.
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spelling pubmed-68481842019-11-19 FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming Wang, Ling Su, Yue Huang, Chang Yin, Yexuan Zhu, Jiaqi Knupp, Alec Chu, Alexander Tang, Young Sci Rep Article FOXH1 is a primitive-streak specifier and ACTIVIN co-effector that plays an important role in development, and positively regulates the generation of human induced pluripotent stem cells (iPSCs) from somatic cells by OCT4, SOX2, KLF4, and MYC (OSKM) transduction. However, the mechanism and upstream regulation for FOXH1 expression in reprogramming are unclear. We found FOXH1 expression plays a significant role to enhance epithelial marker and suppress mesenchymal gene expression in OSKM-mediated human cell reprogramming. Furthermore, NANOG and LIN28 (NL) co-stimulate FOXH1 expression, which correlates with the enhanced reprogramming efficiency by NL-factors. FOXH1 expression is also stimulated by a specific inhibitor for H3K79 methyltransferase DOT1L (iDOT1L) but not by inhibition of the canonical WNT signaling. We further show that blocking endogenous FOXH1 expression eliminates the enhanced reprogramming effect by NL and iDOT1L. However, overexpressing FOXH1 in NL plus iDOT1L condition results in significantly reduced TRA-1-60 positively expressed cells and decreases pluripotent marker expression in reprogramming. Our study elucidated an essential role for properly stimulated FOXH1 expression by NANOG, LIN28, and H3K79 demethylation for dramatic enhancement of reprograming. Nature Publishing Group UK 2019-11-11 /pmc/articles/PMC6848184/ /pubmed/31712708 http://dx.doi.org/10.1038/s41598-019-52861-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Ling
Su, Yue
Huang, Chang
Yin, Yexuan
Zhu, Jiaqi
Knupp, Alec
Chu, Alexander
Tang, Young
FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming
title FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming
title_full FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming
title_fullStr FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming
title_full_unstemmed FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming
title_short FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming
title_sort foxh1 is regulated by nanog and lin28 for early-stage reprogramming
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848184/
https://www.ncbi.nlm.nih.gov/pubmed/31712708
http://dx.doi.org/10.1038/s41598-019-52861-8
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