The role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice.
Maintaining a single active X-chromosome by repressing Xist is crucial for embryonic development in mice. Although the Xist activator RNF12/RLIM is present as a maternal factor, maternal Xist (Xm-Xist) is repressed during preimplantation phases to establish imprinted X-chromosome inactivation (XCI). Here we show, using a highly reproducible chromatin immunoprecipitation method that facilitates chromatin analysis of preimplantation embryos, that H3K9me3 is enriched at the Xist promoter region, preventing Xm-Xist activation by RNF12. The high levels of H3K9me3 at the Xist promoter region are lost in embryonic stem (ES) cells, and ES-cloned embryos show RNF12-dependent Xist expression. Moreover, lack of Xm-XCI in the trophectoderm, rather than loss of paternally expressed imprinted genes, is the primary cause of embryonic lethality in 70-80% of parthenogenotes immediately after implantation. This study reveals that H3K9me3 is involved in the imprinting that silences Xm-Xist. Our findings highlight the role of maternal-specific H3K9me3 modification in embryo development.
Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Atsushi
A
Fukuda
Department of Maternal-Foetal Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Junko
J
Tomikawa
Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Takumi
T
Miura
Department of Maternal-Foetal Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Kenichiro
K
Hata
Department of Maternal-Foetal Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Kazuhiko
K
Nakabayashi
The Howard Hughes Medical Institute, Harvard Stem Cell Institute and the Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Kevin
K
Eggan
Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Hidenori
H
Akutsu
Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Akihiro
A
Umezawa
D000818:Animals; D001755:Blastocyst / Q000502:physiology; D002843:Chromatin / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D056466:Histone Demethylases / Q000378:metabolism* / Q000502:physiology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D062085:RNA, Long Noncoding / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D049951:X Chromosome Inactivation / Q000502:physiology*
D002843:Chromatin; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C511045:Kdm3a protein, mouse; C511781:Kdm4b protein, mouse; C120758:Rlim protein, mouse; D044767:Ubiquitin-Protein Ligases