Kamikawa Yasunao F, Donohoe Mary E
Burke Medical Research Institute, White Plains, New York, United States of America; Department of Neuroscience Brain Mind Research Institute, Weill Cornell Medical College, New York, New York, United States of America; Department of Cell & Development, Weill Cornell Medical College, New York, New York, United States of America.
PLoS One. 2015 May 20;10(5):e0125626. doi: 10.1371/journal.pone.0125626. eCollection 2015.
Epigenetic reprogramming is exemplified by the remarkable changes observed in cellular differentiation and X-chromosome inactivation (XCI) in mammalian female cells. Histone 3 lysine 27 trimethylation (H3K27me3) is a modification that suppresses gene expression in multiple contexts including embryonic stem cells (ESCs) and decorates the entire inactive X-chromosome. The conversion of female somatic cells to induced pluripotency is accompanied by X-chromosome reactivation (XCR) and H3K27me3 erasure. Here, we show that the H3K27-specific demethylase Utx regulates the expression of the master regulators for XCI and XCR: Prdm14, Tsix, and Xist. Female ESC transcriptome analysis using a small molecule inhibitor for H3K27 demethylases, GSK-J4, identifies novel targets of H3K27 demethylation. Consistent with a recent report that GSK-J4 can inhibit other histone demethylase, we found that elevated H3K4me3 levels are associated with increased gene expression including Xist. Our data suggest multiple regulatory mechanisms for XCI via histone demethylation.
表观遗传重编程的例证是在哺乳动物雌性细胞的细胞分化和X染色体失活（XCI）中观察到的显著变化。组蛋白3赖氨酸27三甲基化（H3K27me3）是一种修饰，在包括胚胎干细胞（ESC）在内的多种情况下抑制基因表达，并覆盖整个失活的X染色体。雌性体细胞向诱导多能性的转变伴随着X染色体重新激活（XCR）和H3K27me3擦除。在这里，我们表明H3K27特异性去甲基化酶Utx调节XCI和XCR的主要调节因子的表达：Prdm14、Tsix和Xist。使用H3K27去甲基化酶的小分子抑制剂GSK-J4进行的雌性ESC转录组分析确定了H3K27去甲基化的新靶点。与最近一份关于GSK-J4可抑制其他组蛋白去甲基化酶的报告一致，我们发现H3K4me3水平升高与包括Xist在内的基因表达增加有关。我们的数据表明通过组蛋白去甲基化对XCI存在多种调控机制。
