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Molecular and Cellular Biology, December 2001, p. 8512-8520, Vol. 21, No. 24
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.
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
*
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.
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