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Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency
Background: Long non-coding RNAs (lncRNAs) constitute an important component of the regulatory apparatus that controls stem cell pluripotency. However, the specific mechanisms utilized by these lncRNAs in the control of pluripotency are not fully characterized. Methods: We utilized a RNA reverse tra...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929617/ https://www.ncbi.nlm.nih.gov/pubmed/31903125 http://dx.doi.org/10.7150/thno.39093 |
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author | Wang, Cong Jia, Lin Wang, Yichen Du, Zhonghua Zhou, Lei Wen, Xue Li, Hui Zhang, Shilin Chen, Huiling Chen, Naifei Chen, Jingcheng Zhu, Yanbo Nie, Yuanyuan Celic, Ilkay Gao, Sujun Zhang, Songling Hoffman, Andrew R. Li, Wei Hu, Ji-Fan Cui, Jiuwei |
author_facet | Wang, Cong Jia, Lin Wang, Yichen Du, Zhonghua Zhou, Lei Wen, Xue Li, Hui Zhang, Shilin Chen, Huiling Chen, Naifei Chen, Jingcheng Zhu, Yanbo Nie, Yuanyuan Celic, Ilkay Gao, Sujun Zhang, Songling Hoffman, Andrew R. Li, Wei Hu, Ji-Fan Cui, Jiuwei |
author_sort | Wang, Cong |
collection | PubMed |
description | Background: Long non-coding RNAs (lncRNAs) constitute an important component of the regulatory apparatus that controls stem cell pluripotency. However, the specific mechanisms utilized by these lncRNAs in the control of pluripotency are not fully characterized. Methods: We utilized a RNA reverse transcription-associated trap sequencing (RAT-seq) approach to profile the mouse genome-wide interaction targets for lncRNAs that are screened by RNA-seq. Results: We identified Peblr20 (Pou5F1 enhancer binding lncRNA 20) as a novel lncRNA that is associated with stem cell reprogramming. Peblr20 was differentially transcribed in fibroblasts compared to induced pluripotent stem cells (iPSCs). Notably, we found that Peblr20 utilized a trans mechanism to interact with the regulatory elements of multiple stemness genes. Using gain- and loss-of-function experiments, we showed that knockdown of Peblr20 caused iPSCs to exit from pluripotency, while overexpression of Peblr20 activated endogenous Pou5F1 expression. We further showed that Peblr20 promoted pluripotent reprogramming. Mechanistically, we demonstrated that Peblr20 activated endogenous Pou5F1 by binding to the Pou5F1 enhancer in trans, recruiting TET2 demethylase and activating the enhancer-transcribed RNAs. Conclusions: Our data reveal a novel epigenetic mechanism by which a lncRNA controls the fate of stem cells by trans-regulating the Pou5F1 enhancer RNA pathway. We demonstrate the potential for leveraging lncRNA biology to enhance the generation of stem cells for regenerative medicine. |
format | Online Article Text |
id | pubmed-6929617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-69296172020-01-04 Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency Wang, Cong Jia, Lin Wang, Yichen Du, Zhonghua Zhou, Lei Wen, Xue Li, Hui Zhang, Shilin Chen, Huiling Chen, Naifei Chen, Jingcheng Zhu, Yanbo Nie, Yuanyuan Celic, Ilkay Gao, Sujun Zhang, Songling Hoffman, Andrew R. Li, Wei Hu, Ji-Fan Cui, Jiuwei Theranostics Research Paper Background: Long non-coding RNAs (lncRNAs) constitute an important component of the regulatory apparatus that controls stem cell pluripotency. However, the specific mechanisms utilized by these lncRNAs in the control of pluripotency are not fully characterized. Methods: We utilized a RNA reverse transcription-associated trap sequencing (RAT-seq) approach to profile the mouse genome-wide interaction targets for lncRNAs that are screened by RNA-seq. Results: We identified Peblr20 (Pou5F1 enhancer binding lncRNA 20) as a novel lncRNA that is associated with stem cell reprogramming. Peblr20 was differentially transcribed in fibroblasts compared to induced pluripotent stem cells (iPSCs). Notably, we found that Peblr20 utilized a trans mechanism to interact with the regulatory elements of multiple stemness genes. Using gain- and loss-of-function experiments, we showed that knockdown of Peblr20 caused iPSCs to exit from pluripotency, while overexpression of Peblr20 activated endogenous Pou5F1 expression. We further showed that Peblr20 promoted pluripotent reprogramming. Mechanistically, we demonstrated that Peblr20 activated endogenous Pou5F1 by binding to the Pou5F1 enhancer in trans, recruiting TET2 demethylase and activating the enhancer-transcribed RNAs. Conclusions: Our data reveal a novel epigenetic mechanism by which a lncRNA controls the fate of stem cells by trans-regulating the Pou5F1 enhancer RNA pathway. We demonstrate the potential for leveraging lncRNA biology to enhance the generation of stem cells for regenerative medicine. Ivyspring International Publisher 2020-01-01 /pmc/articles/PMC6929617/ /pubmed/31903125 http://dx.doi.org/10.7150/thno.39093 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Wang, Cong Jia, Lin Wang, Yichen Du, Zhonghua Zhou, Lei Wen, Xue Li, Hui Zhang, Shilin Chen, Huiling Chen, Naifei Chen, Jingcheng Zhu, Yanbo Nie, Yuanyuan Celic, Ilkay Gao, Sujun Zhang, Songling Hoffman, Andrew R. Li, Wei Hu, Ji-Fan Cui, Jiuwei Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency |
title | Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency |
title_full | Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency |
title_fullStr | Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency |
title_full_unstemmed | Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency |
title_short | Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency |
title_sort | genome-wide interaction target profiling reveals a novel peblr20-erna activation pathway to control stem cell pluripotency |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929617/ https://www.ncbi.nlm.nih.gov/pubmed/31903125 http://dx.doi.org/10.7150/thno.39093 |
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