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bioRxiv · 10.1101/2024.07.07.602442

Identification of the sequences responsible for maternal H19-ICR hypermethylation with Beckwith-Wiedemann syndrome-like overgrowth in mice

Hara, S.·Matsuhisa, F.·Kitajima, S.·Yatsuki, H.·Kubiura-Ichimaru, M.·Soejima, H.
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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 responsible for H19-ICR GOM leading to BWS-like overgrowth and are essential for maintaining the unmethylated state of maternal H19-ICR.

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Hara, S., Matsuhisa, F., Kitajima, S., Yatsuki, H., Kubiura-Ichimaru, M., Soejima, H.. 2024-07-10. Identification of the sequences responsible for maternal H19-ICR hypermethylation with Beckwith-Wiedemann syndrome-like overgrowth in mice. https://doi.org/10.1101/2024.07.07.602442

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