Ogawa Yuya, Sun Bryan K, Lee Jeannie T
Department of Molecular Biology, Massachusetts General Hospital and Howard Hughes Medical Institute, Boston, MA 02114, USA.
Science. 2008 Jun 6;320(5881):1336-41. doi: 10.1126/science.1157676.
In mammals, dosage compensation is achieved by X-chromosome inactivation (XCI) in the female. The noncoding Xist gene initiates silencing of the X chromosome, whereas its antisense partner Tsix blocks silencing. The complementarity of Xist and Tsix RNAs has long suggested a role for RNA interference (RNAi). Here, we report that murine Xist and Tsix form duplexes in vivo. During XCI, the duplexes are processed to small RNAs (sRNAs), most likely on the active X (Xa) in a Dicer-dependent manner. Deleting Dicer compromises sRNA production and derepresses Xist. Furthermore, without Dicer, Xist RNA cannot accumulate and histone 3 lysine 27 trimethylation is blocked on the inactive X (Xi). The defects are partially rescued by truncating Tsix. Thus, XCI and RNAi intersect, down-regulating Xist on Xa and spreading silencing on Xi.
在哺乳动物中，雌性通过X染色体失活（XCI）实现剂量补偿。非编码Xist基因启动X染色体的沉默，而其反义伙伴Tsix则阻止沉默。长期以来，Xist和Tsix RNA的互补性表明RNA干扰（RNAi）发挥了作用。在此，我们报告小鼠Xist和Tsix在体内形成双链体。在XCI过程中，双链体被加工成小RNA（sRNA），最有可能是以Dicer依赖的方式在活性X染色体（Xa）上进行。删除Dicer会损害sRNA的产生并解除对Xist的抑制。此外，没有Dicer时，Xist RNA无法积累，并且组蛋白3赖氨酸27三甲基化在失活X染色体（Xi）上被阻断。通过截短Tsix可部分挽救这些缺陷。因此，XCI和RNAi相互交叉，在Xa上下调Xist并在Xi上传播沉默。
