Species Differences in the Structure and Function of the Tsix/TSIX Antisense Gene suggests that its Role is Confined to Imprinted X-inactivation and explains Why X-inactivation is not Imprinted in Human Placenta

Barbara Migeon

The mammalian XIST/Xist gene induces transcriptional silencing of the inactive X chromosome. XIST transcripts start a cascade of events that invariably silences the X chromosome from which they are synthesized (cis inactivation). Therefore, in order to maintain the activity of one X chromosome per cell, it is imperative to turn off one XIST allele in every cell in both sexes. One candidate for the molecules that turn off XIST, so as to protect an X chromosome from cis inactivation, are the transcripts encoded by TSIX/Tsix genes that are antisense to XIST/Xist. There is considerable evidence that murine Tsix is transcribed from the future active X and represses the maternal Xist allele in mouse placenta where X inactivation is parentally imprinted (paternal X always inactive). However, it remains to be seen if this antisense transcript protects the future active X during random inactivation in the embryo proper.

We recently identified human TSIX and showed that it lacks key regulatory elements needed for function of its murine counterpart (1). Now studies of the cellular localization of transcripts in a variety of human cells show that human TSIX is unable to repress XIST in human fetal cells; in fact, it is transcribed from the same chromosome as XIST. Mono-allelically transcribed from the inactive X, TSIX is not maternally imprinted and does not prevent transcription of XIST in cis. Therefore, it seems that the repression of Xist by mouse Tsix has no counterpart in humans and TSIX is not the gene that protects the active X from random inactivation.

The defects in the human gene afford insights into those features of mouse Tsix that are responsible for antisense activity and imprinting.

References:

  1. Migeon, B.R. Am. J. Hum. Genet. 69: 951-960, 2001.