Abstract
It has been recently reported that the regulatory circuitry formed by OCT4, miR-302, and NR2F2 controls both pluripotency and neural differentiation of human embryonic stem cells (hESCs). We show here that JMJD1C, a histone 3 lysine 9 (H3K9) demethylase expressed in hESCs, directly interacts with this circuitry. hESCs with stable knockdown of JMJD1C remain pluripotent while having reduced miR-302 expression, decreased BMP signaling, and enhanced TGFβ signaling. JMJD1C binds to the miR-302 promoter and reduces H3K9 methylation. Withdrawal of basic fibroblast growth factor (bFGF) from the culture induces neural differentiation of the knockdown, but not the control, cells within 3 days, accompanied by elevated NR2F2 expression. This can be attenuated with miR-302 mimics or an H3K9 methytransferase inhibitor. Together, our findings suggest that JMJD1C represses neural differentiation of hESCs at least partially by epigenetically sustaining miR-302 expression and that JMJD1C knockdown is sufficient to trigger neural differentiation upon withdrawal of exogenous bFGF.
Keywords:
Embryonic Stem Cell; Epigenetics; Histone Methylation; MicroRNA; Neurodifferentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / metabolism
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COUP Transcription Factor I / genetics
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COUP Transcription Factor I / metabolism
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Cell Differentiation / physiology*
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Cell Line
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism*
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Epigenesis, Genetic / physiology*
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / metabolism
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Humans
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism*
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MicroRNAs / biosynthesis*
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MicroRNAs / genetics
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Neurons / cytology
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Neurons / metabolism
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism*
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Promoter Regions, Genetic / physiology
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Signal Transduction / physiology*
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
Substances
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Bone Morphogenetic Proteins
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COUP Transcription Factor I
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MIRN302A microRNA, human
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MicroRNAs
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NR2F1 protein, human
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Transforming Growth Factor beta
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Fibroblast Growth Factor 2
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JMJD1C protein, human
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Jumonji Domain-Containing Histone Demethylases
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Oxidoreductases, N-Demethylating