title: Maintenance of Xist Imprinting Depends on Chromatin Condensation State and Rnf12 Dosage in Mice.
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.
authors: Center for Regenerative Medicine, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Fukuda
authors: Center for Regenerative Medicine, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo, Japan.|Department of Molecular Genetics, Kitasato University Graduate School of Medical Sciences, Kitasato, Minami, Sagamihara, Kanagawa, Japan.
authors: Atsushi
authors: A
authors: Mitani
authors: Department of Molecular Genetics, Kitasato University Graduate School of Medical Sciences, Kitasato, Minami, Sagamihara, Kanagawa, Japan.
authors: Toshiyuki
authors: T
authors: Miyashita
authors: Department of Advanced Bioscience, Graduate School of Agriculture, Kindai University, Nakamachi, Nara, Japan.
authors: Takashi
authors: T
authors: Sado
authors: Center for Regenerative Medicine, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo, Japan.
authors: Akihiro
authors: A
authors: Umezawa
authors: Center for Regenerative Medicine, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo, Japan.|Department of Stem Cell Research, Fukushima Medical University, Hikarigaoka, Fukushima City, Fukushima, Japan.
authors: Hidenori
authors: H
authors: Akutsu
mesh_terms: D000818:Animals; D001755:Blastocyst; D002843:Chromatin / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D018392:Genomic Imprinting; D000072741:Maternal Inheritance / Q000235:genetics; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D010312:Parthenogenesis / Q000235:genetics; D000072740:Paternal Inheritance / Q000235:genetics; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: D002843:Chromatin; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D062085:RNA, Long Noncoding; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA; C120758:Rlim protein, mouse; D044767:Ubiquitin-Protein Ligases