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Phenotypic spectrum and extent of DNA methylation defects associated with multi-locus imprinting disturbances

ABSTRACT: Phenotypic spectrum and extent of DNA methylation defects associated with multi-locus imprinting disturbances

PROVIDER: PRJNA314498 | ENA |

REPOSITORIES: ENA

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Phenotypic spectrum and extent of DNA methylation defects associated with multi-locus imprinting disturbances

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-12-31 | GSE78956 | GEO

DNA methylation analysis in multi-locus imprinting disturbances

Project description:The aim of our study was to characterize the genotypic and phenotypic extent of multi-locus imprinting disturbances. Therefore, we analyzed the DNA methylation pattern of 37 individuals with different DNA methylation disturbances. Of these 37 individuals 17 were previously diagnosed with a multi-locus methylation disturbance (MLID) and the remaing 20 were diagnosed with a typical single locus imprinting disorder (SLID). We compared the DNA methylation of these 37 individuals to the DNA methylation of 38 evaluable individuals born small for gestational age. Our analysis revealed 21/37 individuals with a multi-locus methylation disturbances, characterzied by an aberrant DNA methylation in more than one imprintend gene region. Validation analyses were performed by bisulfite-pyrosequencing in the two imprinted gene regions ZDBF2 and FAM50B. Our analyses revealed each one patient previously diagnosed with Temple- and Angelman syndrome to have MLID. Furthermore, we showed that many of the aberrantly methylated imprinted gene regions in patients with MLID are not associated with the so far known typical imprinting disorders.

2016-12-31 | GSE78773 | GEO

Clinical spectrum of multi-locus imprinting disturbances associated with maternal-effect variants range from overt Beckwith-Wiedemann syndrome to apparently healthy phenotype

Project description:Multi-locus imprinting Disturbances (MLID) are methylation defects affecting germline-derived Differentially Methylated Regions (gDMRs) and they have been associated with maternal-effect variants causing imprinting disorders in the offspring. In a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child without any features of imprinting disorders, novel compound heterozygous variants in the NLRP5 gene of the mother were found. Locus-specific and whole-genome methylation analysis by using Infinium MethylationEPIC BeadChip (WG-317-1001, Illumina) revealed MLID with different methylation profiles in both the siblings. The proband and the normal sibling were found to cluster with other MLID cases as shown by principal component analysis and unsupervised hierarchical clustering and remain distinct from controls. However, we were unable to cluster MLID cases associated with specific clinical phenotypes. The identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID add further evidence to the role of NLRP5 in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals.

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Uncovering the phenotypic consequences of multi-locus imprinting disturbances using genome-wide methylation analysis in genomic imprinting disorders

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Systematic analysis of imprinting defects in female and male mouse iPSCs

Project description:Reprogramming of somatic cells into Induced Pluripotent Stem Cells (iPSCs) provided a major leap towards more personalized cellular models for disease modelling and offers great prospects for regenerative medicine. Despite their considerable success, we still lack the ability to control the state of iPSCs fully, especially at the epigenetic level. This can be appreciated at chromosomal regions regulated by genomic imprinting which provides a good read-out for epigenetic fidelity in iPSCs. Indeed, imprinting defects have already been reported in both mouse and human iPSCs. However, the extent, nature, causes and consequences of these defects still remain to be analysed in a systematic manner. To fill this gap in knowledge, we used a controlled secondary reprogramming system whereby the donor mouse embryonic fibroblasts (MEFs) contain a doxycycline (DOX)-inducible Yamanaka cassette and also Single Nucleotide Polymorphisms (SNPs) to distinguish between the two parental alleles. Several female and male isogenic mouse iPSCs (miPSCs) were obtained using independent culture conditions (defined versus serum) and screened by allelic-specific IMPLICON, a targeted next-generation method to measure DNA methylation at imprinted regions with unprecedented genomic coverage of 1000-fold. Our results showed that imprinting defects are remarkably common in miPSCs. Interestingly, we found important differences in gender responses to culture conditions. In particular, female iPSCs exhibit widespread hypomethylation defects regardless of culture conditions, while male miPSCs show tendency for hypomethylation defects under defined conditions, and hypermethylation defects under serum conditions in particular loci. As expected, methylation defects at imprinted regions resulted in dysregulation of monoallelic expression of imprinted genes. Our results are of utmost importance to devise future reprogramming strategies to generate epigenetic error-free iPSCs

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Multi-locus imprinting disturbances in a family harboring a ZFP57 truncation

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Multi-locus imprinting disturbances in a family harboring a ZFP57 truncation

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Analysis of developmental imprinting dynamics in primates using SNP-free methods to identify imprinting defects in cloned placenta

Project description:Our knowledge of genomic imprinting in primates is lagging behand that of mice largely due to the difficulties of allelic analyses in outbred animals. To understand imprinting dynamics in primates, we profiled transcriptomes, DNA methylomes and H3K27me3 in uniparental monkey embryos. We further developed single-nucleotide polymorphisms (SNP)-free methods, TARSII and CARSII, to identify germline differentially methylated regions (DMRs) in somatic tissues. Our comprehensive analyses showed that allelic DNA methylation, but not H3K27me3, is a major mark that correlates with paternal-biasedly expressed genes (PEGs) in uniparental monkey embryos. Interestingly, primate germline DMRs are different from PEG-associated DMRs in early embryos and are enriched in placenta. Strikingly, most placenta-specific germline DMRs are lost in placenta of cloned monkey. Collectively, our study establishes SNP-free germline DMR identification methods, defines developmental imprinting dynamics in primates and demonstrates imprinting defects in cloned monkey placenta, which provides important clues for improving primate cloning.

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