doi: 10

doi: 10.1371/journal.pgen.1003752. 10.4161/rdis.27209 == Recommendations ==. absence of the paternalNdnallele, inNdn+m/-p mice, the maternalNdnallele is usually expressed at an extremely low level with a high degree of non-genetic heterogeneity. In about 50% of these mutant mice, this stochastic expression reduces birth lethality and severity of the breathing deficiency, correlated with a reduction in the loss of serotonergic neurons. Furthermore, using several mouse models, they reveal a competition between non-imprintedNdnpromoters, which results in monoallelic (paternal or maternal)Ndnexpression, suggesting thatNdnmonoallelic expression occurs in the absence of imprinting regulation. Importantly, specific expression of the maternalNDNallele is also detected in post-mortem brain samples of PWS individuals. Here, similar expression of theMagel2maternal allele is usually reported inMagel2+m/-p mice, suggesting that this loss of imprinting can be extended to other PWS genes. These data reveal an unexpected epigenetic flexibility of PWS imprinted genes that could be exploited to reactivate the functional but dormant maternal alleles in PWS. Keywords:imprinting, Prader-Willi, Necdin, Magel2, mouse model Genomic imprinting is usually a normal process of gene regulation revealed in mammals1and flowering plants.2Genomic imprinting leads some autosomal genes to be expressed solely from the maternal inherited chromosomes, as well as others are expressed solely from the paternal inherited chromosomes; thus, the corresponding paternally or maternally inherited alleles, respectively, are silenced. It is a non-Mendelian epigenetic form of gene regulation that is germline-inherited, the epigenetic marks being established in the parental gametes without altering the DNA sequence. The marks are subsequently maintained after fertilization, transmitted through cell division and differentiation and read in the tissue where the parental allele should be repressed.1 Approximately 150 genes are imprinted in mouse and in humans (www.har.mrc.ac.uk/research/genomic-imprinting/), and the vast majority are expressed in placenta and in Clorgyline hydrochloride the brain. At the individual level, a monoallelic expression instead of a biallelic expression should be more deleterious since, when mutated, the functioning allele could not be compensated by the other allele that is silenced; this raises the question about the relevance of genomic imprinting. The reason(s) why this mechanism has been selected/maintained throughout evolution is not clear, although several hypotheses have been put forward.3Obviously, genomic imprinting imposes sexual reproduction since the functional contributions of the paternal and maternal genomes are necessary for normal embryonic and extra-embryonic development.4-6Post-natally, imprinted genes are mainly involved in metabolism,7,8energy homeostasis, and behavior9and play a role in the adaptation to early postnatal life.10A lack of expression of some of these genes is associated with pathologies in human and mouse, and a 2-fold increase in imprinted gene expression can also be found in human disorders, suggesting that expression dosage is critical for at least some Clorgyline hydrochloride imprinted genes.11In view of this, genomic imprinting should be a strong mechanism, reproducible from generation to generation and allowing (1) the monoallelic expression of those paternal or maternal developmental genes necessary for a normal development and (2) a control over gene dosage to prevent both copies being expressed. Paradoxically to this idea of robustness, Clorgyline hydrochloride imprinting regulation is an epigenetic mechanism, and per se, flexibility of this mechanism should be observed in somatic cells. Indeed, imprinted genes have been hypothesized to be vulnerable to environmental perturbation,12,13leading to somatic imprinting alterations and causing several developmental diseases.14It has also been suggested that genomic imprinting allows developmental plasticity in response to environmental conditions.15However in a situation of induced maternal undernutrition, an environmental alteration, imprinted genes appear neither more susceptible to, or more protected from, expression perturbations, either in PP2Bgamma the F1 or F2 generation.8An interesting approach to study the flexibility of genomic.