Relaxation of imprinting in Prader-Willi syndrome

Rogan, Peter K.; Seip, James R.; White, Lisa M.; Wenger, Sharon L.; Steele, Mark W.; Sperling, Mark A.; Menon, Ram K.; Knoll, Joan H.M.

doi:10.1007/s004390050893

Cited by 14 publications

(9 citation statements)

References 41 publications

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“…We visualized asynchronous replication timing by fluorescence in situ hybridization under experimental conditions that separate replicated chromatids (16,17). Imprinted regions have been shown to replicate asynchronously (17,18), with the fraction of asynchronously replicating cells ranging from 21% to 41%, depending on the region analyzed and cell line used. In contrast, nonimprinted regions have shown asynchronous replication in only 9-19% of cells.…”

Section: Resultsmentioning

confidence: 99%

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Mertens¹,

Wolf²,

Tschuch³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Genomic material from chromosome band 13q14.3 distal to the retinoblastoma locus is recurrently lost in a variety of human neoplasms, indicating an as-yet-unidentified tumor-suppressor mechanism. No pathogenic mutations have been found in the minimally deleted region until now. However, in B cell chronic lymphocytic leukemia tumors with loss of one copy of the critical region, respective candidate tumor-suppressor genes are downregulated by a factor >2, which would be expected by a normal gene-dosage effect. This finding points to an epigenetic pathomechanism. We find that the two copies of the critical region replicate asynchronously, suggesting differential chromatin packaging of the two copies of 13q14.3. Although we also detect monoallelic silencing of genes localized in the critical region, monoallelic expression originates from either the maternal or paternal copy, excluding an imprinting mechanism. DNA methylation analyses revealed one CpG island of the region to be methylated. DNA demethylation of this CpG island and global histone hyperacetylation induced biallelic expression, whereas replication timing was not affected. We propose that differential replication timing represents an early epigenetic mark that distinguishes the two copies of 13q14.3, resulting in differential chromatin packaging and monoallelic expression. Accordingly, deletion of the single active copy of 13q14.3 results in significant downregulation of the candidate genes and loss of function, providing a model for the interaction of genetic lesions and epigenetic silencing at 13q14.3 in B cell chronic lymphocytic leukemia.DNA methylation ͉ monoallelic expression ͉ replication timing

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Section: Resultsmentioning

confidence: 99%

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Mertens¹,

Wolf²,

Tschuch³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…These observations indicate that the SNRPN promoter region regulates imprinting not only of SNRPN, but also of the entire region. This is also supported by the finding that PWS patients harbouring translocations with breakpoints telomeric of SNRPN exhibit proper imprinting of SNRPN but not of genes distal of the translocation breakpoints100.…”

Section: Imprinting Switching In Prader–willi and Angelman Syndromesmentioning

confidence: 58%

DNA methylation in genomic imprinting, development, and disease

2001

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Changes in DNA methylation profiles are common features of development and in a number of human diseases, such as cancer and imprinting disorders like Beckwith-Wiedemann and Prader-Willi/Angelman syndromes. This suggests that DNA methylation is required for proper gene regulation during development and in differentiated tissues and has clinical relevance. DNA methylation is also involved in X-chromosome inactivation and the allele-specific silencing of imprinted genes. This review describes possible mechanisms by which DNA methylation can regulate gene expression, using imprinted genes as examples. The molecular basis of methylationmediated gene regulation is related to changes in chromatin structure and appears to be similar for both imprinted and biallelically expressed genes.

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“…However, in brains of mice, with a deletion of the imprinting center, an incomplete silencing of paternally inherited PWS genes as well as a low level of expression of maternal alleles of PWS genes, was reported but not investigated [27]. LOI was also observed in lymphoblasts of two PWS patients with a deletion and two atypical PWS patients with a maternal disomy [28], [29], but these studies were not extended to include expression profiles in the brain. LOI has been described in other contexts, particularly in some cancers [30].…”

Section: Discussionmentioning

confidence: 99%

Stochastic Loss of Silencing of the Imprinted Ndn/NDN Allele, in a Mouse Model and Humans with Prader-Willi Syndrome, Has Functional Consequences

et al. 2013

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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.

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Relaxation of imprinting in Prader-Willi syndrome

Cited by 14 publications

References 41 publications

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

DNA methylation in genomic imprinting, development, and disease

Stochastic Loss of Silencing of the Imprinted Ndn/NDN Allele, in a Mouse Model and Humans with Prader-Willi Syndrome, Has Functional Consequences

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