Howard Hughes Medical Institute, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2010 Oct 29;143(3):390-403. doi: 10.1016/j.cell.2010.09.049.
Once protein-coding, the X-inactivation center (Xic) is now dominated by large noncoding RNAs (ncRNA). X chromosome inactivation (XCI) equalizes gene expression between mammalian males and females by inactivating one X in female cells. XCI requires Xist, an ncRNA that coats the X and recruits Polycomb proteins. How Xist is controlled remains unclear but likely involves negative and positive regulators. For the active X, the antisense Tsix RNA is an established Xist repressor. For the inactive X, here, we identify Xic-encoded Jpx as an Xist activator. Jpx is developmentally regulated and accumulates during XCI. Deleting Jpx blocks XCI and is female lethal. Posttranscriptional Jpx knockdown recapitulates the knockout, and supplying Jpx in trans rescues lethality. Thus, Jpx is trans-acting and functions as ncRNA. Furthermore, ΔJpx is rescued by truncating Tsix, indicating an antagonistic relationship between the ncRNAs. We conclude that Xist is controlled by two RNA-based switches: Tsix for Xa and Jpx for Xi.
一旦编码蛋白质，X 失活中心（Xic）现在主要由大型非编码 RNA（ncRNA）组成。X 染色体失活（XCI）通过在雌性细胞中失活一条 X 染色体，使哺乳动物雌雄之间的基因表达均等化。XCI 需要 Xist，这是一种覆盖 X 染色体并招募 Polycomb 蛋白的 ncRNA。Xist 的控制方式尚不清楚，但可能涉及负调控因子和正调控因子。对于活性 X，反义 Tsix RNA 是一种已确定的 Xist 抑制剂。对于失活 X，我们在这里鉴定出 Xic 编码的 Jpx 是 Xist 的激活剂。Jpx 受发育调控，并在 XCI 过程中积累。删除 Jpx 会阻止 XCI，并导致雌性致死。Jpx 的转录后敲低可再现敲除，而转染 Jpx 可挽救致死性。因此，Jpx 是反式作用并作为 ncRNA 发挥功能。此外，ΔJpx 可被截断的 Tsix 挽救，表明这两种 ncRNA 之间存在拮抗关系。我们得出结论，Xist 受两个基于 RNA 的开关控制：Tsix 用于 Xa，Jpx 用于 Xi。
