Long non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling.
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.
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Department of Spine Surgery, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai 200003, China.
Chen
0000-0001-8068-2109
C
Xu
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Yan
Y
Zhang
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Qiaoling
Q
Wang
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Zhenyu
Z
Xu
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Junfeng
J
Jiang
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reprodutive Medcine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China.
Yuping
Y
Gao
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reprodutive Medcine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China.
Minzhi
M
Gao
School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Jiuhong
J
Kang
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Minjuan
M
Wu
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Jun
J
Xiong
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Kaihong
K
Ji
Department of Spine Surgery, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai 200003, China.
Wen
W
Yuan
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Yue
Y
Wang
Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.|Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai 200433, China.
Houqi
H
Liu
D002460:Cell Line; D000066673:Cell Self Renewal / Q000235:genetics*; D055785:Gene Knockdown Techniques; D000066449:Human Embryonic Stem Cells / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D055457:Nodal Protein / Q000235:genetics* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics
C561567:GAS5 long non-coding RNA, human; D035683:MicroRNAs; C526007:NODAL protein, human; D055457:Nodal Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D062085:RNA, Long Noncoding; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors