From the Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030 and.
J Biol Chem. 2014 Jan 24;289(4):2384-95. doi: 10.1074/jbc.M113.535799. Epub 2013 Dec 6.
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.
最近有报道称，OCT4、miR-302 和 NR2F2 组成的调控回路控制着人类胚胎干细胞（hESC）的多能性和神经分化。我们在这里表明，JMJD1C，一种在 hESC 中表达的组蛋白 3 赖氨酸 9（H3K9）去甲基化酶，直接与这个回路相互作用。稳定敲低 JMJD1C 的 hESC 保持多能性，同时 miR-302 表达降低，BMP 信号减弱，TGFβ信号增强。JMJD1C 结合到 miR-302 启动子上，降低 H3K9 甲基化。从培养物中去除碱性成纤维细胞生长因子（bFGF）会在 3 天内诱导敲低的细胞而不是对照细胞向神经分化，同时 NR2F2 表达升高。这可以通过 miR-302 模拟物或 H3K9 甲基转移酶抑制剂来减弱。总之，我们的发现表明，JMJD1C 通过表观遗传维持 miR-302 的表达，从而抑制 hESC 的神经分化，而敲低 JMJD1C 足以在外源 bFGF 去除后触发神经分化。
