Models for the coordinate regulation of Xist DNA methylation and expression by Tsix, de novo DNA methyltransferases and Dicer. De novo DNA methyltransferases (Dnmt) promote methylation of Xist DNA. Increased Xist expression, as is seen in the Xist promoter mutants, could trigger Xist DNA hypomethylation (a) indirectly by affecting Tsix RNA levels, if Tsix is necessary to direct de novo DNA methyltransferases to the Xist gene, or (b) directly, if Xist RNA can interfere with de novo DNA methyltransferase activity locally. (c) Because Dicer deficiency causes a global decrease in levels of de novo DNA methyltransferases, Dicer must lie directly upstream of the de novo DNA methyltransferases and need not function through either Xist or Tsix to regulate Xist DNA methylation. (The DNA is shown as methylated in a, b and c (bottom), although in a and b if the inhibitory interactions between Xist and Tsix RNA (a) or Dmt (b) prevail, the DNA will be hypomethylated.)

Transcription of Xist and Tsix on the X chromosome. The coding sequences of Xist and Tsix overlap on opposite strands of the X-chromosome DNA.