Epigenetic Regulation of miR-302 by JMJD1C Inhibits Neural Differentiation of Human Embryonic Stem Cells |
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| Authors: | Jianle Wang Jung W Park Hicham Drissi Xiaofang Wang Ren-He Xu |
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| Institution: | From the ‡Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030 and ;the §Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut 06030 |
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| 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. |
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| Keywords: | Embryonic Stem Cell Epigenetics Histone Methylation MicroRNA Neurodifferentiation |
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