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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
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.
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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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