Transcription Is Required to Establish Maternal Imprinting at the Prader-Willi Syndrome and Angelman Syndrome Locus

University of Cambridge, United Kingdom
PLoS Genetics (Impact Factor: 8.17). 12/2011; 7(12):e1002422. DOI: 10.1371/journal.pgen.1002422
Source: PubMed

ABSTRACT The Prader-Willi syndrome (PWS [MIM 17620]) and Angelman syndrome (AS [MIM 105830]) locus is controlled by a bipartite imprinting center (IC) consisting of the PWS-IC and the AS-IC. The most widely accepted model of IC function proposes that the PWS-IC activates gene expression from the paternal allele, while the AS-IC acts to epigenetically inactivate the PWS-IC on the maternal allele, thus silencing the paternally expressed genes. Gene order and imprinting patterns at the PWS/AS locus are well conserved from human to mouse; however, a murine AS-IC has yet to be identified. We investigated a potential regulatory role for transcription from the Snrpn alternative upstream exons in silencing the maternal allele using a murine transgene containing Snrpn and three upstream exons. This transgene displayed appropriate imprinted expression and epigenetic marks, demonstrating the presence of a functional AS-IC. Transcription of the upstream exons from the endogenous locus correlates with imprint establishment in oocytes, and this upstream exon expression pattern was conserved on the transgene. A transgene bearing targeted deletions of each of the three upstream exons exhibited loss of imprinting upon maternal transmission. These results support a model in which transcription from the Snrpn upstream exons directs the maternal imprint at the PWS-IC.

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Available from: James L Resnick, Aug 09, 2015
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    • "There is also evidence for the presence of a corresponding U-exon in the human AS-IC region, which might allow for a similar mechanism of transcription/RNA mediated epigenetic modification (Farber et al., 1999). As with the Gnas locus, it remains unclear whether the RNA is required or whether the process of transcription through the Snrpn promoter suffices, to establish the epigenetic/imprinting mark at the PWS-IC (Chotalia et al., 2009; Smith et al., 2011). However, the functional similarities in oocytes between the U-exons of Snrpn and Nesp of the Gnas locus are evident, and it has been shown recently that transcription is a common feature associated with the establishment of DNA methylation in oocytes (Smallwood et al., 2011). "
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