An Unexpected Function of the Prader-Willi Syndrome Imprinting Center in Maternal Imprinting in Mice

Mei-Yi Wu,Ming Jiang,Ray-Chang Wu,Xiaodong Zhai,Arthur L Beaudet

doi:10.1371/journal.pone.0034348

Mei-Yi Wu, Ming Jiang + Show 3 more

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https://doi.org/10.1371/journal.pone.0034348

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Abstract

Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11–q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted domain, the mouse equivalent of the human AS-IC element has not yet been identified. Here, we suggest another dimension that the PWS-IC also functions in maternal imprinting by negatively regulating the paternally expressed imprinted genes in mice, in contrast to its known function as a positive regulator for paternal-specific gene expression. Using a mouse model carrying a 4.8-kb deletion at the PWS-IC, we demonstrated that maternal transmission of the PWS-IC deletion resulted in a maternal imprinting defect with activation of the paternally expressed imprinted genes and decreased expression of the maternally expressed imprinted gene on the maternal chromosome, accompanied by alteration of the maternal epigenotype toward a paternal state spread over the PWS/AS domain. The functional significance of this acquired paternal pattern of gene expression was demonstrated by the ability to complement PWS phenotypes by maternal inheritance of the PWS-IC deletion, which is in stark contrast to paternal inheritance of the PWS-IC deletion that resulted in the PWS phenotypes. Importantly, low levels of expression of the paternally expressed imprinted genes are sufficient to rescue postnatal lethality and growth retardation in two PWS mouse models. These findings open the opportunity for a novel approach to the treatment of PWS.

Highlights

Genomic imprinting regulates gene expression only from one allele that is inherited either from the mother or from the father
To study the maternal imprinting features regulated by the Prader-Willi syndrome (PWS)-IC, we investigated the maternal pattern of gene expression in the mouse model with the PWS-IC D4.8 mutation at Snrpn exon 1
The analysis of maternal-specific expression of the Snrpn transcripts was accomplished in mice with paternal inheritance of a deletion spanning from exon 2 of Snrpn to Ube3a (DS-U) [28]

Summary

Introduction

Genomic imprinting regulates gene expression only from one allele that is inherited either from the mother or from the father. The PWS/AS imprinted domain contains a number of paternally expressed genes, including MKRN3, MAGEL2, NDN, C15ORF2, SNURF-SNRPN, and C/D box small nucleolar RNAs (snoRNAs) SNORD107, SNORD64, SNORD108, SNORD109A, SNORD116, SNORD115, and SNORD109B [1]. SnoRNAs are encoded within these large SNRPN sense/UBE3A antisense and Snrpn sense/Ube3a antisense transcripts derived from both SNRPN/Snrpn major and upstream alternative promoters. SNORD116/Snord116 and SNORD115/ Snord115 are present as multiple copy gene clusters Among these paternally expressed imprinted genes, SNORD116 plays a major role in PWS etiology, because deficiency of this gene caused the key characteristics of the PWS phenotype in human [9,10,11]. UBE3A is the AS gene and encodes E6-AP ubiquitin-protein ligase expressed preferentially from the maternal chromosome in brains [16,17]. Mutations of the Ube3a in mice resulted in the phenotype resembling human AS [18,19]

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