Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02214, USA.
Genetics. 2012 Nov;192(3):857-68. doi: 10.1534/genetics.112.144121. Epub 2012 Aug 31.
In the early mammalian embryo, X chromosome inactivation (XCI) achieves dosage parity between males and females for X-linked genes. During mouse development, imprinted paternal XCI is observed first and switches to random XCI in the epiblast but not placental lineages. The mechanism by which this epigenetic switch occurs is currently unknown. Here, we establish an ex vivo model for imprinting and identify a novel trans-acting regulatory factor for imprinted XCI. Using an induced trophoblast stem cell (iTS) model, we show that embryonic stem (ES) cells transdifferentiated into trophoblasts retain partial memory of the XCI imprint. Cdx2, a stem cell factor that determines commitment to the extraembryonic lineage, directly binds Xist and activates expression of Xist RNA in extrembryonic cells. Cdx2 competes with Oct4, a stem cell factor that determines commitment to the embryonic lineage, for overlapping binding sites within Xist. We propose that mutually exclusive binding between Cdx2 and Oct4 in Xist underlies the switch between imprinted and random XCI in the early mouse embryo.
在早期哺乳动物胚胎中，X 染色体失活（XCI）实现了 X 连锁基因在男性和女性之间的剂量平衡。在小鼠发育过程中，首先观察到印迹的父本 XCI，并在胚胎外胚层而不是胎盘谱系中转换为随机 XCI。目前尚不清楚这种表观遗传开关发生的机制。在这里，我们建立了一个印迹的体外模型，并鉴定了一个新的印迹 XCI 的反式作用调节因子。使用诱导滋养层干细胞（iTS）模型，我们表明胚胎干细胞（ES）细胞转分化为滋养细胞后仍保留部分 XCI 印迹的记忆。Cdx2 是一个决定外胚层谱系的干细胞因子，它直接与 Xist 结合并激活 Xist RNA 在极端胚胎细胞中的表达。Cdx2 与 Oct4（决定胚胎谱系的干细胞因子）竞争重叠的 Xist 内结合位点。我们提出，Cdx2 和 Oct4 在 Xist 之间的相互排斥结合是早期小鼠胚胎中印迹和随机 XCI 之间转换的基础。
