Sado Takashi, Okano Masaki, Li En, Sasaki Hiroyuki
Division of Human Genetics, National Institute of Genetics, 1111 Yata, Mishima 411-8540, Japan.
Development. 2004 Mar;131(5):975-82. doi: 10.1242/dev.00995.
Xist (X-inactive specific transcript) plays a crucial role in X-inactivation. This non-coding RNA becomes upregulated on the X chromosome that is to be inactivated upon differentiation. Previous studies have revealed that although maintenance-type DNA methylation is not essential for X-inactivation to occur, it is required for the stable repression of Xist in differentiated cells. However, it is unknown whether differential de novo methylation at the Xist promoter, which is mediated by Dnmt3a and/or Dnmt3b, is a cause or a consequence of monoallelic expression of Xist. We show that Xist expression is appropriately regulated in the absence of Dnmt3a and Dnmt3b and that a single X chromosome undergoes proper inactivation in mutant females. Our results indicate that a mechanism(s) other than DNA methylation plays a principal role in initiating X-inactivation. We also demonstrate that delayed upregulation of Xist does not induce X-inactivation, consistent with a crucial developmental window for the chromosomal silencing.
Xist（X染色体失活特异性转录本）在X染色体失活过程中起着关键作用。这种非编码RNA在分化时即将失活的X染色体上表达上调。先前的研究表明，虽然维持型DNA甲基化对于X染色体失活的发生并非必需，但对于分化细胞中Xist的稳定抑制却是必需的。然而，由Dnmt3a和/或Dnmt3b介导的Xist启动子处的差异从头甲基化是Xist单等位基因表达的原因还是结果尚不清楚。我们发现，在没有Dnmt3a和Dnmt3b的情况下，Xist表达受到适当调控，并且在突变雌性个体中，单条X染色体能够正常失活。我们的结果表明，除DNA甲基化外的其他机制在启动X染色体失活中起主要作用。我们还证明，Xist的延迟上调不会诱导X染色体失活，这与染色体沉默的关键发育窗口一致。
