Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth
Abstract Beckwith-Wiedemann syndrome (BWS) is caused by a gain of methylation (GOM) at the imprinting control region within the Igf2-H19 domain on the maternal allele (H19-ICR GOM). Mutations in the binding sites of several transcription factors are involved in H19-ICR GOM and BWS. However, the resp...
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Nature Portfolio
2024-12-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07323-x |
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| author | Satoshi Hara Fumikazu Matsuhisa Shuji Kitajima Hitomi Yatsuki Musashi Kubiura-Ichimaru Ken Higashimoto Hidenobu Soejima |
| author_facet | Satoshi Hara Fumikazu Matsuhisa Shuji Kitajima Hitomi Yatsuki Musashi Kubiura-Ichimaru Ken Higashimoto Hidenobu Soejima |
| author_sort | Satoshi Hara |
| collection | DOAJ |
| description | Abstract Beckwith-Wiedemann syndrome (BWS) is caused by a gain of methylation (GOM) at the imprinting control region within the Igf2-H19 domain on the maternal allele (H19-ICR GOM). Mutations in the binding sites of several transcription factors are involved in H19-ICR GOM and BWS. However, the responsible sequence(s) for H19-ICR GOM with BWS-like overgrowth has not been identified in mice. Here, we report that a mutation in the SOX-OCT binding site (SOBS) causes partial H19-ICR GOM, which does not extend beyond CTCF binding site 3 (CTS3). Moreover, simultaneously mutating both SOBS and CTS3 causes complete GOM of the entire H19-ICR, leading to the misexpression of the imprinted genes, and frequent BWS-like overgrowth. In addition, CTS3 is critical for CTCF/cohesin-mediated chromatin conformation. These results indicate that SOBS and CTS3 are the sequences in which mutations cause H19-ICR GOM leading to BWS-like overgrowth and are essential for maintaining the unmethylated state of maternal H19-ICR. |
| format | Article |
| id | doaj-art-0ed67d3c001f4f32b0cf08bb4096cf53 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-0ed67d3c001f4f32b0cf08bb4096cf532025-08-20T02:20:44ZengNature PortfolioCommunications Biology2399-36422024-12-017111210.1038/s42003-024-07323-xIdentification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowthSatoshi Hara0Fumikazu Matsuhisa1Shuji Kitajima2Hitomi Yatsuki3Musashi Kubiura-Ichimaru4Ken Higashimoto5Hidenobu Soejima6Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga UniversityDivision of Biological Resources and Development, Analytical Research Center for Experimental Sciences, Saga UniversityDivision of Biological Resources and Development, Analytical Research Center for Experimental Sciences, Saga UniversityDivision of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga UniversityDivision of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga UniversityDivision of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga UniversityDivision of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga UniversityAbstract Beckwith-Wiedemann syndrome (BWS) is caused by a gain of methylation (GOM) at the imprinting control region within the Igf2-H19 domain on the maternal allele (H19-ICR GOM). Mutations in the binding sites of several transcription factors are involved in H19-ICR GOM and BWS. However, the responsible sequence(s) for H19-ICR GOM with BWS-like overgrowth has not been identified in mice. Here, we report that a mutation in the SOX-OCT binding site (SOBS) causes partial H19-ICR GOM, which does not extend beyond CTCF binding site 3 (CTS3). Moreover, simultaneously mutating both SOBS and CTS3 causes complete GOM of the entire H19-ICR, leading to the misexpression of the imprinted genes, and frequent BWS-like overgrowth. In addition, CTS3 is critical for CTCF/cohesin-mediated chromatin conformation. These results indicate that SOBS and CTS3 are the sequences in which mutations cause H19-ICR GOM leading to BWS-like overgrowth and are essential for maintaining the unmethylated state of maternal H19-ICR.https://doi.org/10.1038/s42003-024-07323-x |
| spellingShingle | Satoshi Hara Fumikazu Matsuhisa Shuji Kitajima Hitomi Yatsuki Musashi Kubiura-Ichimaru Ken Higashimoto Hidenobu Soejima Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth Communications Biology |
| title | Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth |
| title_full | Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth |
| title_fullStr | Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth |
| title_full_unstemmed | Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth |
| title_short | Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth |
| title_sort | identification of responsible sequences which mutations cause maternal h19 icr hypermethylation with beckwith wiedemann syndrome like overgrowth |
| url | https://doi.org/10.1038/s42003-024-07323-x |
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