DNA methylation regulates long-range gene silencing of an X-linked homeobox gene cluster in a lineage-specific manner.
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 ( approximately 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.
Oda
Masaaki
M
Laboratory for Mammalian Epigenetic Studies, Center for Developmental Biology, RIKEN, Kobe, Hyogo, 650-0047, Japan.
Yamagiwa
Akiko
A
Yamamoto
Shinji
S
Nakayama
Takao
T
Tsumura
Akiko
A
Sasaki
Hiroshi
H
Nakao
Kazuki
K
Li
En
E
Okano
Masaki
M
D000818:Animals; D019070:Cell Lineage; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004622:Embryo, Mammalian / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D005801:Genes, Homeobox; D050172:Genes, X-Linked; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse