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Targeted mutagenesis of Tsix leads to nonrandom X inactivation

J T Lee1, N Lu

  • 1Department of Molecular Biology, Massachusetts General Hospital, Boston 02115, USA. lee@molbio.mgh.harvard.edu

Cell
|October 16, 1999
PubMed

Insights

The Tsix gene regulates X chromosome inactivation choice in mammals. Deleting Tsix in female cells skewed X chromosome inactivation, showing Tsix controls Xist expression without affecting silencing.

Area of Science:

  • Genetics
  • Epigenetics
  • Mammalian Development

Background:

  • Mammalian female cells undergo X inactivation, randomly selecting one X chromosome to silence.
  • The long noncoding RNA Xist is upregulated on the inactive X chromosome.
  • The antisense gene Tsix is hypothesized to regulate Xist expression.

Purpose of the Study:

  • To investigate the role of the Tsix gene in controlling X chromosome inactivation.
  • To determine if Tsix regulates Xist expression and influences X chromosome choice.

Main Methods:

  • Targeted deletion of the Tsix gene in female (XX) and male (XY) mouse cells.
  • Analysis of X chromosome counting, Xist expression, and inactivation patterns.

Main Results:

  • Tsix deficiency did not affect X chromosome counting in either XX or XY cells.
  • Heterozygous female cells with Tsix deletion showed skewed Xist expression and preferential inactivation of the mutant X.
  • The mutant X chromosome's ability to block Xist accumulation was compromised.

Conclusions:

  • Tsix acts in cis to regulate Xist expression and determine X chromosome choice.
  • X chromosome counting, choice, and silencing are genetically separable processes.
  • Distinct negative and positive factors likely mediate active and inactive X chromosome selection in XX and XY cells.

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