Hara Satoshi, Matsuhisa Fumikazu, Kitajima Shuji, Yatsuki Hitomi, Kubiura-Ichimaru Musashi, Higashimoto Ken, Soejima Hidenobu
Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.
Division of Biological Resources and Development, Analytical Research Center for Experimental Sciences, Saga University, Saga, 849-8501, Japan.
Commun Biol. 2024 Dec 2;7(1):1605. doi: 10.1038/s42003-024-07323-x.
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.
贝克威思-维德曼综合征（BWS）是由母源等位基因上Igf2-H19结构域内印记控制区的甲基化增加（GOM）（H19-ICR GOM）引起的。几种转录因子结合位点的突变与H19-ICR GOM和BWS有关。然而，在小鼠中尚未鉴定出与BWS样过度生长相关的H19-ICR GOM的责任序列。在此，我们报告SOX-OCT结合位点（SOBS）的突变会导致部分H19-ICR GOM，其不会延伸超过CTCF结合位点3（CTS3）。此外，同时突变SOBS和CTS3会导致整个H19-ICR完全GOM，导致印记基因的错误表达以及频繁出现BWS样过度生长。另外，CTS3对于CTCF/黏连蛋白介导的染色质构象至关重要。这些结果表明，SOBS和CTS3是其中的突变会导致H19-ICR GOM从而导致BWS样过度生长的序列，并且对于维持母源H19-ICR的未甲基化状态至关重要。
