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Methylation analysis of the PWS/AS region does not support an enhancer-competition model

Nature Genetics volume 19, pages 324–325 (1998)Cite this article

In a recent article in Nature Genetics1, Tilghman et al. propose an enhancer-competition model to explain genomic imprinting in the Prader-Willi/Angelman syndrome (PWS/AS) region on human chromosome 15. The key elements of this model are as follows: (i) the minimal imprinting centre (IC) region deleted in AS patients with an imprinting defect (AS-SRO) is extensively methylated in the female germ line and induces post-fertilization spreading of DNA methylation along the maternal chromosome; (ii) the minimal IC region deleted in PWS patients with an imprinting defect (PWS-SRO), which contains the SNRPN promoter, functions in the soma to maintain the entire PWS region in an unmethylated state; (iii) SNRPN and the AS gene (UBE3A) compete for a neuronal enhancer. The authors claim that their model is simpler than the model proposed by Dittrich et al.2, which suggests that maternal imprinting requires the AS-SRO in cis and an XX-specific factor in trans, and that the PWS-SRO is the 'imprint switch initiation site'.

Furthermore, Glenn et al.5 and Buiting et al.6 have demonstrated that CpG dinucleotides in intron 7 of the human SNRPN gene and 15 kb upstream of the AS-SRO (Y48.5) are methylated on the paternal chromosome and undermethylated on the maternal chromosome. Paternal methylation of these sites and biallelic methylation of the AS-SRO does not support the second statement of Tilghman et al. claiming that the SNRPN promoter functions in the soma to maintain the entire PWS region in an unmethylated state.

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Figure 1: Physical map of the imprinting centre and methylation status of HpaII and CfoI sites.
Figure 2: Methylation status of the AS-SRO as determined by genomic sequencing.

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Acknowledgements

We thank C. Färber for helpful discussions. This research was supported by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie through the Center for Molecular Medicine Köln (W.D.) and by the Deutsche Forschungsgemeinschaft (B.H.).

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Authors and Affiliations

  1. Institut für Genetik, Universität zu Köln, Germany

    Axel Schumacher, Michael Zeschnigk & Walter Doerfler

  2. Institut für Humangenetik, Universitätsklinikum Essen, Germany

    Karin Buiting, Michael Zeschnigk & Bernhard Horsthemke

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  1. Axel Schumacher
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Correspondence to Bernhard Horsthemke.

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Schumacher, A., Buiting, K., Zeschnigk, M. et al. Methylation analysis of the PWS/AS region does not support an enhancer-competition model. Nat Genet 19, 324–325 (1998). https://doi.org/10.1038/1211

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