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The imprinting box of the Prader-Willi/Angelman syndrome domain

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Abstract

A subset of mammalian genes is monoallelically expressed in a parent-of-origin manner. These genes are subject to an imprinting process that epigenetically marks alleles according to their parental origin during gametogenesis. Imprinted genes can be organized in clusters as exemplified by the 2-Mb domain on human chromosome 15q11–q13 and its mouse orthologue on chromosome 7c (ref. 1). Loss of this 2-Mb domain on the paternal or maternal allele results in two neurogenetic disorders, Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Microdeletions on the paternal allele share a 4.3-kb short region of overlap (SRO), which includes the SNRPN promoter/exon1, cause PWS and silence paternally expressed genes2. Microdeletions on the maternal allele share a 0.88-kb SRO located 35 kb upstream to the SNRPN promoter3, cause AS and alleviate repression of genes on the maternal allele4. Individuals carrying both AS and PWS deletions on the paternal allele show a PWS phenotype and genotype. These observations suggest that cis elements within the AS-SRO and PWS-SRO constitute an imprinting box that regulates the entire domain on both chromosomes. Here we show that a minitransgene composed of a 200-bp Snrpn promoter/exon1 and a 1-kb sequence located approximately 35 kb upstream to the SNRPN promoter confer imprinting as judged by differential methylation, parent-of-origin–specific transcription and asynchronous replication.

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Figure 1: Methylation of the Snrpn promoter within a 1.2-kb DMR1 transgene.
Figure 2: Methylation of the Snrpn promoter in the P1 clone transgene.
Figure 3: Methylation of the Snrpn promoter within the AS-SMP transgene.
Figure 4: Methylation, expression and replication timing data.
Figure 5: Regional control at the PWS/AS domain.

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Acknowledgements

We thank B. Horsthemke for comments. The work was supported by the Israel Science Foundation-Centers of Excellence Program, the NIH (A.R. and H.C.), the Israel Ministry of Health (A.R. and R.S.) and the US–Israel Binational Science Foundation (H.C.). A.Y.H. was partially supported by a Foulkes Foundation fellowship.

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Authors and Affiliations

  1. Department of Cellular Biochemistry and Human Genetics, The Hebrew University Hadassah Medical School, Jerusalem, Israel

    Ruth Shemer, Alon Y. Hershko, Jonathan Perk, Raul Mostoslavsky, Ben-zion Tsuberi, Howard Cedar & Aharon Razin

  2. Institute for Human Genetics, University Clinic, Essen, Germany

    Karin Buiting

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  1. Ruth Shemer
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  2. Alon Y. Hershko
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  3. Jonathan Perk
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  4. Raul Mostoslavsky
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  5. Ben-zion Tsuberi
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  6. Howard Cedar
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  7. Karin Buiting
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  8. Aharon Razin
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Correspondence to Aharon Razin.

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Shemer, R., Hershko, A., Perk, J. et al. The imprinting box of the Prader-Willi/Angelman syndrome domain. Nat Genet 26, 440–443 (2000). https://doi.org/10.1038/82571

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