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Molecular and Cellular Biology, May 2007, p. 3750-3757, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02204-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mbd2 Contributes to DNA Methylation-Directed Repression of the Xist Gene{triangledown}

Helen Barr, Andrea Hermann, Jennifer Berger, Hsin-Hao Tsai, Karen Adie, Anna Prokhortchouk, Brian Hendrich, and Adrian Bird*

Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, King's Buildings, Edinburgh EH9 3JR, United Kingdom

Received 24 November 2006/ Returned for modification 2 January 2007/ Accepted 1 March 2007

Transcription of the Xist gene triggers X chromosome inactivation in cis and is therefore silenced on the X chromosome that remains active. DNA methylation contributes to this silencing, but the mechanism is unknown. As methylated DNA binding proteins (MBPs) are potential mediators of gene silencing by DNA methylation, we asked whether MBP-deficient cell lines could maintain Xist repression. The absence of Mbd2 caused significant low-level reactivation of Xist, but silencing was restored by exogenous Mbd2. In contrast, deficiencies of Mbd1, MeCP2, and Kaiso had no detectable effect, indicating that MBPs are not functionally redundant at this locus. Xist repression in Mbd2-null cells was hypersensitive to the histone deacetylase inhibitor trichostatin A and to depletion of the DNA methyltransferase Dnmt1. These synergies implicate Mbd2 as a mediator of the DNA methylation signal at this locus. The presence of redundant mechanisms to enforce repression at Xist and other loci is compatible with the hypothesis that "stacking" of imperfect repressive tendencies may be an evolutionary strategy to ensure leakproof gene silencing.

* Corresponding author. Mailing address: Wellcome Trust Centre for Cell Biology, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, United Kingdom. Phone: 0131-650-5670. Fax: 0131-650-5379. E-mail: a.bird{at}ed.ac.uk

{triangledown} Published ahead of print on 12 March 2007.

Molecular and Cellular Biology, May 2007, p. 3750-3757, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02204-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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