Lopes, S. et al. Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions. Hum. Mol. Genet. 12, 295-305

Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK.
Human Molecular Genetics (Impact Factor: 6.39). 03/2003; 12(3):295-305. DOI: 10.1093/hmg/ddg022
Source: PubMed


Imprinted genes and their control elements occur in clusters in the mammalian genome and carry epigenetic modifications. Observations from imprinting disorders suggest that epigenetic modifications throughout the clusters could be under regional control. However, neither the elements that are responsible for regional control, nor its developmental timing, particularly whether it occurs in the germline or postzygotically, are known. Here we examine regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline specific methylation was reprogrammed after fertilization in two differentially methylated regions (DMRs) in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, we found that the DMRs themselves are involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination. These observations are likely to be relevant to other gene clusters in which epigenetic regulation plays a role, and in pathological situations in which epigenetic regulation is disrupted.

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    • "). DNMT mutant mice exhibit loss of methylation and perturbed imprinting (Biniszkiewicz et al. 2002; Kaneda et al. 2004a; Kato et al. 2007), and mice knockouts for specific germline DMRs have demonstrated that these serve as imprinting control regions for the locus (Thorvaldsen et al. 1998; Bielinska et al. 2000; Fitzpatrick et al. 2002; Lopes et al. 2003; da Rocha et al. 2008). The mouse has been the primary species for determining DMR germline origin (Supplemental Table 6). "
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    ABSTRACT: Genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. Defects in normal imprinting are found in cancer, assisted reproductive technologies, and several human syndromes. In mouse models, germline-derived DNA methylation is shown to regulate imprinting. Though imprinting is largely conserved between mammals, species- and tissue-specific domains of imprinted expression exist. Using the cynomolgus macaque (Macaca fascicularis) to assess primate-specific imprinting, we present a comprehensive view of tissue-specific imprinted expression and DNA methylation at established imprinted gene clusters. For example, like mouse and unlike human, macaque IGF2R is consistently imprinted, and the PLAGL1, INPP5F transcript variant 2, and PEG3 imprinting control regions are not methylated in the macaque germline but acquire this post-fertilization. Methylome data from human early embryos appear to support this finding. These suggest fundamental differences in imprinting control mechanisms between primate species and rodents at some imprinted domains, with implications for our understanding of the epigenetic programming process in humans and its influence on disease. © 2015 Cheong et al.; Published by Cold Spring Harbor Laboratory Press.
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    • "Furthermore, biallelic methylation at the Zdbf2 DMR in offspring derived from Dnmt3L mat-/- mothers correlated with biallelic expression of Zdbf2. While the exact mechanism responsible for the parental allele-specific acquisition of DNA methylation at secondary DMRs has not yet been determined, it is clear that there is a relationship between the epigenetic states at primary and secondary DMRs [9,10]. "
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    ABSTRACT: Background Differential distribution of DNA methylation on the parental alleles of imprinted genes distinguishes the alleles from each other and dictates their parent of origin-specific expression patterns. While differential DNA methylation at primary imprinting control regions is inherited via the gametes, additional allele-specific DNA methylation is acquired at secondary sites during embryonic development and plays a role in the maintenance of genomic imprinting. The precise mechanisms by which this somatic DNA methylation is established at secondary sites are not well defined and may vary as methylation acquisition at these sites occurs at different times for genes in different imprinting clusters. Results In this study, we show that there is also variability in the timing of somatic DNA methylation acquisition at multiple sites within a single imprinting cluster. Paternal allele-specific DNA methylation is initially acquired at similar stages of post-implantation development at the linked Dlk1 and Gtl2 differentially methylated regions (DMRs). In contrast, unlike the Gtl2-DMR, the maternal Dlk1-DMR acquires DNA methylation in adult tissues. Conclusions These data suggest that the acquisition of DNA methylation across the Dlk1/Gtl2 imprinting cluster is variable. We further found that the Dlk1 differentially methylated region displays low DNA methylation fidelity, as evidenced by the presence of hemimethylation at approximately one-third of the methylated CpG dyads. We hypothesize that the maintenance of DNA methylation may be less efficient at secondary differentially methylated sites than at primary imprinting control regions.
    Full-text · Article · May 2014 · Epigenetics & Chromatin
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    • "However, the germline status of most human imprinted DMRs is currently unknown. Several germline DMRs have been shown to govern postzygotic secondary DMRs that are regulated in a hierarchical fashion [Coombes et al., 2003; Kagami et al., 2010; Lopes et al., 2003]. In all cases to date, the imprinted methylation profile is maintained irrespective of gene expression levels, with some imprinted transcripts being highly expressed during embryonic development and showing a temporal decrease after birth [Iglesias-Platas et al., 2012]. "
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    ABSTRACT: Genomic imprinting is the parent-of-origin specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies, since it is evident that aberrant pre-implantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina Goldengate array targeting 27 imprinted-DMRs we profiled allelic methylation in 65 imprinting defect patients. We identify multi-locus hypomethyaltion in numerous BWS, TNDM and PHP-1B patients, and an individual with SRS. Our data reveals a broad range of epimutations exist in certain imprinting syndromes, with the exception of PWS and AS patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the aetiology of imprint establishment and maintenance.
    Full-text · Article · Feb 2013 · Human Mutation
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