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Molecular and Cellular Biology, December 2001, p. 8512-8520, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8512-8520.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Antisense Transcription through the Xist Locus Mediates Tsix Function in Embryonic Stem Cells

Sandra Luikenhuis,1 Anton Wutz,2 and Rudolf Jaenisch1,2,*

Department of Biology, Massachusetts Institute of Technology,1 and Whitehead Institute for Biomedical Research,2 Cambridge, Massachusetts 02142

Received 5 July 2001/Returned for modification 22 August 2001/Accepted 6 September 2001

Expression of the Xist gene, a key player in mammalian X inactivation, has been proposed to be controlled by the antisense Tsix transcript. Targeted deletion of the Tsix promoter encompassing the DPXas34 locus leads to nonrandom inactivation of the mutant X, but it remains unresolved whether this phenotype is caused by loss of Tsix transcription or by deletion of a crucial DNA element. In this study we determined the role of Tsix transcription in random X inactivation by using mouse embryonic stem (ES) cells as a model system. Two approaches were chosen to modulate Tsix transcription with minimal disturbance of genomic sequences. First, Tsix transcription was functionally inhibited by introducing a transcriptional stop signal into the transcribed region of Tsix. In the second approach, an inducible system for Tsix expression was created. We found that the truncation of the Tsix transcript led to complete nonrandom inactivation of the targeted X chromosome. Induction of Tsix transcription during ES cell differentiation, on the other hand, caused the targeted chromosome always to be chosen as the active chromosome. These results for the first time establish a function for antisense transcription in the regulation of X inactivation.

* Corresponding author. Mailing address: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. Phone: (617) 258-5186. Fax: (617) 258-6505. E-mail: jaenisch{at}wi.mit.edu.

Molecular and Cellular Biology, December 2001, p. 8512-8520, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8512-8520.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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