Mbd2 contributes to DNA methylation-directed repression of the Xist gene

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 Dnmtl. 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.

Original languageEnglish
Pages (from-to)3750-3757
Number of pages8
JournalMolecular and Cellular Biology
Issue number10
Publication statusPublished - May 2007


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