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First published online February 18, 2004
doi: 10.1242/10.1242/dev.00995

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De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation

¹ Division of Human Genetics, National Institute of Genetics, 1111 Yata, Mishima, 411-8540, Japan
² Department of Biosystems Science, The Graduate School for Advanced Studies (SOKENDAI)
³ PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, Japan
⁴ Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA
⁵ Department of Genetics, The Graduate School for Advanced Studies (SOKENDAI)

^* Author for correspondence (e-mail: tsado{at}lab.nig.ac.jp)

Accepted 12 November 2003

Xist (X-inactive specific transcript) plays a crucial role in X-inactivation. This non-coding RNA becomes upregulated on the X chromosome that is to be inactivated upon differentiation. Previous studies have revealed that although maintenance-type DNA methylation is not essential for X-inactivation to occur, it is required for the stable repression of Xist in differentiated cells. However, it is unknown whether differential de novo methylation at the Xist promoter, which is mediated by Dnmt3a and/or Dnmt3b, is a cause or a consequence of monoallelic expression of Xist. We show that Xist expression is appropriately regulated in the absence of Dnmt3a and Dnmt3b and that a single X chromosome undergoes proper inactivation in mutant females. Our results indicate that a mechanism(s) other than DNA methylation plays a principal role in initiating X-inactivation. We also demonstrate that delayed upregulation of Xist does not induce X-inactivation, consistent with a crucial developmental window for the chromosomal silencing.

Key words: X chromosome inactivation, De novo DNA methyltransferases, Xist

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