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DNA methylation regulates long-range gene silencing of an X-linked homeobox gene cluster in a lineage-specific manner

¹ Laboratory for Mammalian Epigenetic Studies, Center for Developmental Biology, RIKEN, Kobe, Hyogo, 650-0047, Japan; ² Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN, Kobe, Hyogo, 650-0047, Japan; ³ Laboratory for Embryonic Induction, Center for Developmental Biology, RIKEN, Kobe, Hyogo, 650-0047, Japan; ⁴ Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; ⁵ Epigenetics Program, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA

DNA methylation is a major epigenetic mechanism that has been suggested to control developmental gene regulation during embryogenesis, but its regulatory mechanisms remain unclear. In this report, we show that CpG islands associated with the X-linked homeobox gene cluster Rhox, which is highly expressed in the extraembryonic trophectoderm, are differentially methylated in a stage- and lineage-specific manner during the post-implantation development of mice. Inactivation of both Dnmt3a and Dnmt3b, DNA methyltransferases essential for the initiation of de novo DNA methylation, abolished the establishment of DNA methylation and the silencing of Rhox cluster genes in the embryo proper. The Dnmt3-dependent CpG-island methylation at the Rhox locus extended for a large genomic region (1 Mb) containing the Rhox cluster and surrounding genes. Complementation experiments using embryonic stem (ES) cells deficient in the DNA methyltransferases suggested that the CpG-island methylation by Dnmt3a and Dnmt3b was restricted within this large genomic region, and did not affect the neighboring genes outside it, implicating the existence of region-specific boundaries. Our results suggest that DNA methylation plays important roles in both long-range gene silencing and lineage-specific silencing in embryogenesis.

[Keywords: DNA methylation; Dnmt3a; Dnmt3b; Rhox]

Received July 18, 2006; revised version accepted October 30, 2006.

E-MAIL okano{at}cdb.riken.jp; FAX 81-78-306-3167.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1470906

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