Species-specific differences in X chromosome inactivation in mammals

Sado, Takashi; Sakaguchi, Takehisa

doi:10.1530/rep-13-0173

Cited by 29 publications

(25 citation statements)

References 80 publications

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“…Previously, Sado and Sakaguchi proposed that chromatin condensation states in parental genomes differed in each specie and that this might define imprinted XCI [34]. In the current study, we showed that the asymmetric chromatin condensation states of parental Xist / Tsix genomic regions are crucial for the initiation of Xist expression in mice (Fig 7b).…”

Section: Discussionsupporting

confidence: 68%

Maintenance of Xist Imprinting Depends on Chromatin Condensation State and Rnf12 Dosage in Mice

et al. 2016

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In female mammals, activation of Xist (X-inactive specific transcript) is essential for establishment of X chromosome inactivation. During early embryonic development in mice, paternal Xist is preferentially expressed whereas maternal Xist (Xm-Xist) is silenced. Unlike autosomal imprinted genes, Xist imprinting for Xm-Xist silencing was erased in cloned or parthenogenetic but not fertilized embryos. However, the molecular mechanism underlying the variable nature of Xm-Xist imprinting is poorly understood. Here, we revealed that Xm-Xist silencing depends on chromatin condensation states at the Xist/Tsix genomic region and on Rnf12 expression levels. In early preimplantation, chromatin decondensation via H3K9me3 loss and histone acetylation gain caused Xm-Xist derepression irrespective of embryo type. Although the presence of the paternal genome during pronuclear formation impeded Xm-Xist derepression, Xm-Xist was robustly derepressed when the maternal genome was decondensed before fertilization. Once Xm-Xist was derepressed by chromatin alterations, the derepression was stably maintained and rescued XmXpΔ lethality, indicating that loss of Xm-Xist imprinting was irreversible. In late preimplantation, Oct4 served as a chromatin opener to create transcriptional permissive states at Xm-Xist/Tsix genomic loci. In parthenogenetic embryos, Rnf12 overdose caused Xm-Xist derepression via Xm-Tsix repression; physiological Rnf12 levels were essential for Xm-Xist silencing maintenance in fertilized embryos. Thus, chromatin condensation and fine-tuning of Rnf12 dosage were crucial for Xist imprint maintenance by silencing Xm-Xist.

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Section: Discussionsupporting

confidence: 68%

Maintenance of Xist Imprinting Depends on Chromatin Condensation State and Rnf12 Dosage in Mice

et al. 2016

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“…Although early studies suggest that the choice for which X-chromosome is inactivated is random (43), later studies on female carriers of specific X-linked mutations showed skewed patterns of XCI resulting from negative selection of cells harboring the lethal allele in the active state (44). Furthermore, X-chromosome skewing is a common feature of tumorigenic processes in which an acquired somatic mutation occurs in a single progenitor cell that subsequently undergoes clonal expansion and gives rise to progeny with the same XCI pattern (44, 45). …”

Section: Resultsmentioning

confidence: 99%

Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects

Myklebust

Damme

Støve

et al. 2014

Human Molecular Genetics

112

149

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The X-linked lethal Ogden syndrome was the first reported human genetic disorder associated with a mutation in an N-terminal acetyltransferase (NAT) gene. The affected males harbor an Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. Structural models and molecular dynamics simulations of the human NatA and its S37P mutant highlight differences in regions involved in catalysis and at the interface between Naa10 and the auxiliary subunit hNaa15. Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 S37P and Naa15 as well as Naa50 (NatE), another interactor of the NatA complex. N-Terminal acetylome analyses revealed a decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells, supporting the genetic findings and our hypothesis regarding reduced Nt-acetylation of a subset of NatA/NatE-type substrates as one etiology for Ogden syndrome. Furthermore, Ogden syndrome fibroblasts display abnormal cell migration and proliferation capacity, possibly linked to a perturbed retinoblastoma pathway. N-Terminal acetylation clearly plays a role in Ogden syndrome, thus revealing the in vivo importance of N-terminal acetylation in human physiology and disease.

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“…If the chromatin structure of the maternal Xist locus needs further cell division to become similar to that of the paternal locus, this would account for the lag in the timing of maternal Xist CAG being upregulated relative to paternal Xist CAG . Such a difference in the chromatin structure, if any, may also be relevant to the monoallelic upregulation of Xist in wild-type female embryos in favor of the paternal allele during preimplantation development (Sado and Sakaguchi, 2013). In other words, the maternal Xist allele was repressed during early cleavage stages because it was not yet ready for transcription owing to the compact chromatin structure being inaccessible by transcription factors.…”

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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Species-specific differences in X chromosome inactivation in mammals

Cited by 29 publications

References 80 publications

Maintenance of Xist Imprinting Depends on Chromatin Condensation State and Rnf12 Dosage in Mice

Maintenance of Xist Imprinting Depends on Chromatin Condensation State and Rnf12 Dosage in Mice

Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects

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

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