Abstract
The pluripotency of embryonic stem cells (ESCs) is controlled by a multilayer regulatory network, of which the key factors include core pluripotency genes Oct4, Sox2 and Nanog, and multiple microRNAs (miRNAs). Recently, long noncoding RNAs (lncRNAs) have been discovered as a class of new regulators for ESCs, and some lncRNAs could function as competing endogenous RNAs (ceRNAs) to regulate mRNAs by competitively binding to miRNAs. Here, we identify mmu-miR-139-5p as a new regulator for Nanog by targeting Nanog 3' untranslated region (UTR) to repress Nanog expression in mouse ESCs and embryos. Such regulation could be released by an ESC-specifically expressed ceRNA named lnc-NAP. The expression of lnc-NAP is activated by OCT4, SOX2, as well as NANOG through promoter binding. Downregulation of lnc-NAP reduces Nanog abundance, which leads to decreased pluripotency of mouse ESCs and embryonic lethality. These results reveal lnc-NAP as a new regulator for Nanog in mouse ESCs, and uncover a feed-forward regulatory loop of Nanog through the participation of lnc-NAP.
Keywords:
Nanog; ceRNA; lncRNA; miR-139-5p; microRNA; pluripotency.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / genetics
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Animals
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Cell Differentiation / genetics
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Embryo, Mammalian / cytology
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Embryo, Mammalian / embryology
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Embryo, Mammalian / metabolism*
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism*
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Gene Expression Regulation, Developmental*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Inbred NOD
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Mice, SCID
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MicroRNAs / genetics*
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Nanog Homeobox Protein / genetics*
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Nanog Homeobox Protein / metabolism
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Promoter Regions, Genetic / genetics
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Protein Binding
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RNA, Long Noncoding / genetics*
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RNA-Seq / methods
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Reverse Transcriptase Polymerase Chain Reaction / methods
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
Substances
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3' Untranslated Regions
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MIRN139 microRNA, mouse
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MicroRNAs
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Nanog Homeobox Protein
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Nanog protein, mouse
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Octamer Transcription Factor-3
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Pou5f1 protein, mouse
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RNA, Long Noncoding
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SOXB1 Transcription Factors
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Sox2 protein, mouse
Grants and funding
This work was supported by grants from Chinese Academy of Sciences (QYZDJ-SSW-SMC015 to X.-J.W.), National Natural Science Foundation of China (91839105 to M.W., 81790622 and 91940304 to X.-J.W.), and CAS Strategic Priority Research Program (XDA16020801 to X.-J.W.).