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PLoS Genet. 2016 Oct 27;12(10):e1006375. doi: 10.1371/journal.pgen.1006375. eCollection 2016 Oct.

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

Author information

1
Center for Regenerative Medicine, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo, Japan.
2
Department of Molecular Genetics, Kitasato University Graduate School of Medical Sciences, Kitasato, Minami, Sagamihara, Kanagawa, Japan.
3
Department of Advanced Bioscience, Graduate School of Agriculture, Kindai University, Nakamachi, Nara, Japan.
4
Department of Stem Cell Research, Fukushima Medical University, Hikarigaoka, Fukushima City, Fukushima, Japan.

Abstract

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.

PMID:
27788132
PMCID:
PMC5082930
DOI:
10.1371/journal.pgen.1006375
[Indexed for MEDLINE]
Free PMC Article

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