Long non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling

Chen Xu, Yan Zhang, Qiaoling Wang, Zhenyu Xu, Junfeng Jiang, Yuping Gao, Minzhi Gao, Jiuhong Kang, Minjuan Wu, Jun Xiong, Kaihong Ji, Wen Yuan, Yue Wang () and Houqi Liu ()
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Chen Xu: Research Center of Developmental Biology, Second Military Medical University
Yan Zhang: Research Center of Developmental Biology, Second Military Medical University
Qiaoling Wang: Research Center of Developmental Biology, Second Military Medical University
Zhenyu Xu: Research Center of Developmental Biology, Second Military Medical University
Junfeng Jiang: Research Center of Developmental Biology, Second Military Medical University
Yuping Gao: Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reprodutive Medcine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Minzhi Gao: Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reprodutive Medcine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Jiuhong Kang: School of Life Sciences and Technology, Tongji University
Minjuan Wu: Research Center of Developmental Biology, Second Military Medical University
Jun Xiong: Research Center of Developmental Biology, Second Military Medical University
Kaihong Ji: Research Center of Developmental Biology, Second Military Medical University
Wen Yuan: Changzheng Hospital Affiliated to Second Military Medical University
Yue Wang: Research Center of Developmental Biology, Second Military Medical University
Houqi Liu: Research Center of Developmental Biology, Second Military Medical University

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: Abstract Long non-coding RNAs (lncRNAs) are known players in the regulatory circuitry of the self-renewal in human embryonic stem cells (hESCs). However, most hESC-specific lncRNAs remain uncharacterized. Here we demonstrate that growth-arrest-specific transcript 5 (GAS5), a known tumour suppressor and growth arrest-related lncRNA, is highly expressed and directly regulated by pluripotency factors OCT4 and SOX2 in hESCs. Phenotypic analysis shows that GAS5 knockdown significantly impairs hESC self-renewal, but its overexpression significantly promotes hESC self-renewal. Using RNA sequencing and functional analysis, we demonstrate that GAS5 maintains NODAL signalling by protecting NODAL expression from miRNA-mediated degradation. Therefore, we propose that the above pluripotency factors, GAS5 and NODAL form a feed-forward signalling loop that maintains hESC self-renewal. As this regulatory function of GAS5 is stem cell specific, our findings also indicate that the functions of lncRNAs may vary in different cell types due to competing endogenous mechanisms.

Date: 2016
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DOI: 10.1038/ncomms13287

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