The role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice

Fukuda, Atsushi; Tomikawa, Junko; Miura, Takumi; Hata, Kenichiro; Nakabayashi, Kazuhiko; Eggan, Kevin; Akutsu, Hidenori; Umezawa, Akihiro

doi:10.1038/ncomms6464

Cited by 55 publications

(77 citation statements)

References 39 publications

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“…Recently, Fukuda et al demonstrated that overexpression of Kdm4b, a histone demethylase for H3K9me3, can induce upregulation of Xist from the 4-cell stage in parthenogenetically activated embryos (Fukuda et al, 2014). This suggests, in fact, that global demethylation of H3K9me3 and subsequent alteration of the chromatin structure facilitate derepression of Xist on Xm otherwise repressed.…”

Section: Discussionmentioning

confidence: 99%

A new Xist allele driven by a constitutively active promoter is dominated by Xist locus environment and exhibits the parent-of-origin effects

et al. 2015

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The dosage difference of X-linked genes between the sexes in mammals is compensated for by genetic inactivation of one of the X chromosomes in XX females. A noncoding RNA transcribed from the Xist gene at the onset of X chromosome inactivation coats the X chromosome in cis and induces chromosome-wide heterochromatinization. Here, we report a new Xist allele (Xist CAG ) driven by a CAG promoter, which is known to be constitutively active in many types of cells. The paternal transmission of Xist CAG resulted in the preferential inactivation of the targeted paternal X (Xp) not only in the extra-embryonic but also the embryonic lineage, whereas maternal transmission ended with embryonic lethality at the early postimplantation stage with a phenotype that resembled mutant embryos carrying a maternal deficiency in Tsix, an antisense negative regulator of Xist, in both sexes. Interestingly, we found that the upregulation of Xist CAG in preimplantation embryos temporally differed depending on its parental origin: its expression started at the 4-to 8-cell stages when paternally inherited, and Xist CAG was upregulated at the blastocyst stage when maternally inherited. This might indicate that the Xist locus on Xp is permissive to transcription, but the Xist locus on the maternal X (Xm) is not. We extrapolated from these findings that the maternal Xist allele might manifest a chromatin structure inaccessible by transcription factors relative to the paternal allele. This might underlie the mechanism for the maternal repression of Xist at the early cleavage stage when Tsix expression has not yet occurred on Xm.

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Section: Discussionmentioning

confidence: 99%

A new Xist allele driven by a constitutively active promoter is dominated by Xist locus environment and exhibits the parent-of-origin effects

et al. 2015

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“…The H3K9me3 mark is required to counteract the function of the Xist activator RNF12/RLIM on the Xm [41], which is deposited maternally in the oocyte and which is required for expression of Xist on the Xp during imprinted XCI [42]. However, it seems that H3K9me3 is not the primary imprinting mark, as there is no difference in H3K9me3 at the Xist promoter before and after oocyte growth, when the imprint is established [43].…”

Section: Imprinted XCImentioning

confidence: 93%

“…Like NANOG, PRDM14 binds to Xist intron 1 and the Rnf12 promoter in ESCs [47,84], where it represses Rnf12 by recruiting the PRC2 complex, which lies down the H3K27me3 mark. As RNF12 is essential for imprinted XCI [41,42] and gets downregulated in the epiblast [103], this could provide a mechanism, how Xist is repressed during XCR. A facilitating role in the XCR process in the blastocyst plays the Xist repressor Tsix, which becomes biallelically expressed in the epiblast during XCR [45,104].…”

Section: Resetting the Xci--stage By X--chromosome Reactivation (Xcr)mentioning

confidence: 99%

“…Mechanistically, trimethylation of histone H3 lysine 9 (H3K9me3) at the Xist promoter on the Xm in preimplantation embryos is critical to keep Xist silent and thereby the Xm active [41]. The H3K9me3 mark is required to counteract the function of the Xist activator RNF12/RLIM on the Xm [41], which is deposited maternally in the oocyte and which is required for expression of Xist on the Xp during imprinted XCI [42].…”

Section: Imprinted XCImentioning

confidence: 99%

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Developmental regulation of X-chromosome inactivation

Payer

2016

Seminars in Cell & Developmental Biology

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With the emergence of sex--determination by sex chromosomes, which differ in composition and number between males and females, appeared the need to equalize X--chromosomal gene dosage between the sexes. Mammals have devised the strategy of X--chromosome inactivation (XCI), in which one of the two X--chromosomes is rendered transcriptionally silent in females. In the mouse, the best--studied model organism with respect to XCI, this inactivation process occurs in different forms, imprinted and random, interspersed by periods of X--chromosome reactivation (XCR), which is needed to switch between the different modes of XCI. In this review, I describe the recent advances with respect to the developmental control of XCI and XCR and in particular their link to differentiation and pluripotency. Furthermore, I review the mechanisms, which influence the timing and choice, with which one of the two X--chromosomes is chosen for inactivation during random XCI. This has an impact on how females are mosaics with regard to which X--chromosome is active in different cells, which has implications on the severity of diseases caused by X--linked mutations.

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“…Little is known about the maternal imprint. Although de novo DNA methylation is dispensable (28), Xist's antisense partner, Tsix, plays a critical role in protecting the X M from silencing (29)(30)(31), and the H3K9me3 mark correlates with Xist silencing (32).…”

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confidence: 99%

Xist imprinting is promoted by the hemizygous (unpaired) state in the male germ line

Sun

Payer

Namekawa

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2015. Contributed by Jeannie T. Lee, October 1, 2015 (sent for review July 29, 2015; reviewed by Nora Engel and Kathrin Plath)The long noncoding X-inactivation-specific transcript (Xist gene) is responsible for mammalian X-chromosome dosage compensation between the sexes, the process by which one of the two X chromosomes is inactivated in the female soma. Xist is essential for both the random and imprinted forms of X-chromosome inactivation. In the imprinted form, Xist is paternally marked to be expressed in female embryos. To investigate the mechanism of Xist imprinting, we introduce Xist transgenes (Tg) into the male germ line. Although ectopic high-level Xist expression on autosomes can be compatible with viability, transgenic animals demonstrate reduced fitness, subfertility, defective meiotic pairing, and other germ-cell abnormalities. In the progeny, paternal-specific expression is recapitulated by the 200-kb Xist Tg. However, Xist imprinting occurs efficiently only when it is in an unpaired or unpartnered state during male meiosis. When transmitted from a hemizygous father (+/Tg), the Xist Tg demonstrates paternalspecific expression in the early embryo. When transmitted by a homozygous father (Tg/Tg), the Tg fails to show imprinted expression. Thus, Xist imprinting is directed by sequences within a 200-kb X-linked region, and the hemizygous (unpaired) state of the Xist region promotes its imprinting in the male germ line.Xist | imprinting | X inactivation | transgenerational inheritance | meiotic silencing by unpaired DNA

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The role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice

Cited by 55 publications

References 39 publications

A new Xist allele driven by a constitutively active promoter is dominated by Xist locus environment and exhibits the parent-of-origin effects

A new Xist allele driven by a constitutively active promoter is dominated by Xist locus environment and exhibits the parent-of-origin effects

Developmental regulation of X-chromosome inactivation

Xist imprinting is promoted by the hemizygous (unpaired) state in the male germ line

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