title: Stochastic loss of silencing of the imprinted Ndn/NDN allele, in a mouse model and humans with prader-willi syndrome, has functional consequences.
abstract: Genomic imprinting is a process that causes genes to be expressed from one allele only according to parental origin, the other allele being silent. Diseases can arise when the normally active alleles are not expressed. In this context, low level of expression of the normally silent alleles has been considered as genetic noise although such expression has never been further studied. Prader-Willi Syndrome (PWS) is a neurodevelopmental disease involving imprinted genes, including NDN, which are only expressed from the paternally inherited allele, with the maternally inherited allele silent. We present the first in-depth study of the low expression of a normally silent imprinted allele, in pathological context. Using a variety of qualitative and quantitative approaches and comparing wild-type, heterozygous and homozygous mice deleted for Ndn, we show that, in absence of the paternal Ndn allele, the maternal Ndn allele is expressed at an extremely low level with a high degree of non-genetic heterogeneity. The level of this expression is sex-dependent and shows transgenerational epigenetic inheritance. In about 50% of mutant mice, this expression reduces birth lethality and severity of the breathing deficiency, correlated with a reduction in the loss of serotonergic neurons. In wild-type brains, the maternal Ndn allele is never expressed. However, using several mouse models, we reveal a competition between non-imprinted Ndn promoters which results in monoallelic (paternal or maternal) Ndn expression, suggesting that Ndn allelic exclusion occurs in the absence of imprinting regulation. Importantly, specific expression of the maternal NDN allele is also detected in post-mortem brain samples of PWS individuals. Our data reveal an unexpected epigenetic flexibility of PWS imprinted genes that could be exploited to reactivate the functional but dormant maternal alleles in PWS. Overall our results reveal high non-genetic heterogeneity between genetically identical individuals that might underlie the variability of the phenotype.
authors.affiliation: INSERM, Institut de Neurobiologie de la Méditerranée (INMED) U901, Marseille, France ; Aix-Marseille Université, INMED UMR901, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rieusset
authors.forename: Fabienne
authors.initials: F
authors.lastname: Schaller
authors.forename: Unga
authors.initials: U
authors.lastname: Unmehopa
authors.forename: Valery
authors.initials: V
authors.lastname: Matarazzo
authors.forename: Françoise
authors.initials: F
authors.lastname: Watrin
authors.forename: Matthias
authors.initials: M
authors.lastname: Linke
authors.forename: Beatrice
authors.initials: B
authors.lastname: Georges
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Bischof
authors.forename: Femke
authors.initials: F
authors.lastname: Dijkstra
authors.forename: Monique
authors.initials: M
authors.lastname: Bloemsma
authors.forename: Severine
authors.initials: S
authors.lastname: Corby
authors.forename: François J
authors.initials: FJ
authors.lastname: Michel
authors.forename: Rachel
authors.initials: R
authors.lastname: Wevrick
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zechner
authors.forename: Dick
authors.initials: D
authors.lastname: Swaab
authors.forename: Keith
authors.initials: K
authors.lastname: Dudley
authors.forename: Laurent
authors.initials: L
authors.lastname: Bezin
authors.forename: Françoise
authors.initials: F
authors.lastname: Muscatelli
mesh_terms: D000483:Alleles; D000818:Animals; D001049:Apnea / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D006579:Heterozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C069766:necdin
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