Maternal methylation imprints on human chromosome 15 are established during or after fertilization

El‐Maarri, Osman; Buiting, Karin; Peery, Edwin G.; Kroisel, Peter M.; Balaban, Başak; Wagner, Klaus; Urman, Bülent; Heyd, Julia; Lich, Christina; Brannan, Camilynn I.; Walter, Jörn; Horsthemke, Bernhard

doi:10.1038/85927

Cited by 192 publications

(153 citation statements)

References 20 publications

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“…2 and Fig. S4), indicating that the methylation imprint at the PWS-IC is not erased or reset during the nuclear reprogramming process in both male and female iPSC lines, supports the widely accepted model that the PWS-IC methylation imprint is erased in the germline, established either in the germline or during the early stages of preimplantation development, and then maintained throughout development (25)(26)(27)(28). These findings suggest that the PWS-IC methylation imprint is refractory to the global erasure of epigenetic marks induced by the reprogramming process.…”

Section: As and Pws Ipscs Maintain The Appropriate Methylation Imprintmentioning

confidence: 51%

Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader–Willi syndromes

Chamberlain

Chen²,

Ng³

et al. 2010

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

286

257

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Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurodevelopmental disorders of genomic imprinting. AS results from loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, whereas the genetic defect in PWS is unknown. Although induced pluripotent stem cells (iPSCs) provide invaluable models of human disease, nuclear reprogramming could limit the usefulness of iPSCs from patients who have AS and PWS should the genomic imprint marks be disturbed by the epigenetic reprogramming process. Our iPSCs derived from patients with AS and PWS show no evidence of DNA methylation imprint erasure at the cis-acting PSW imprinting center. Importantly, we find that, as in normal brain, imprinting of UBE3A is established during neuronal differentiation of AS iPSCs, with the paternal UBE3A allele repressed concomitant with up-regulation of the UBE3A antisense transcript. These iPSC models of genomic imprinting disorders will facilitate investigation of the AS and PWS disease processes and allow study of the developmental timing and mechanism of UBE3A repression in human neurons.antisense transcript | epigenetic | neuronal differentiation A ngelman syndrome (AS) is a neurogenetic disorder characterized by profound intellectual disability, absent speech, frequent seizures, motor dysfunction, and a characteristic happy demeanor (1, 2). Prader-Willi syndrome (PWS) is characterized hyperphagia/obesity; small stature, hands, and feet; and behavioral problems that are likened to obsessive compulsive disorder (3). AS is caused by loss of function of the maternally inherited allele of the E3 ubiquitin ligase UBE3A. UBE3A is subject to tissuespecific genomic imprinting; although both alleles are expressed in most tissues, the paternally inherited allele is repressed in the brain (4-6). Imprinted expression of UBE3A is thought to occur as a result of reciprocal expression of a long noncoding antisense transcript, UBE3A-ATS, which is part of a >600-kb transcript initiating at the differentially methylated PWS imprinting center (IC) located in exon 1 of the SNURF-SNRPN gene (7-9). PWS is associated with the loss of several species of small nucleolar RNAs (snoRNAs) (10); however, its genetic basis is currently unknown, and there is no mouse model that recapitulates all features of PWS.Mouse models of AS have proved significant in studying important aspects of the AS disease mechanism. There are, however, differences in the tissue specificity of the transcript that harbors UBE3A-ATS between humans and mice (11), indicating that the timing and mechanism of UBE3A repression may diverge between these species. The ability to study the developmental timing and mechanism of brain-specific repression of the paternal UBE3A allele in a model of human development is critical for better understanding the AS disease process and for using live neurons from patients with AS to discover previously undescribed therapeutic interventions. Here, we have developed such a model via human induced pluripotent stem cell (iPSC)-technology. ResultsHu...

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Section: As and Pws Ipscs Maintain The Appropriate Methylation Imprintmentioning

confidence: 51%

Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader–Willi syndromes

Chamberlain

Chen²,

Ng³

et al. 2010

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

286

257

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“…Recently, it was revealed that histone modifications are important to determine whether the DNA methylation occurs (Tamaru et al, 2001;Jackson et al, 2002). It is proposed that histone methylation at lysine 9 is a gametic imprint in the imprinting center PWS-IC (Xin et al, 2001), while cytosine methylation of the PWS-IC occurs only after fertilization (El-Maarri et al, 2001).…”

Section: Dna Methylation In Various Biological Phenomenamentioning

confidence: 99%

Gene silencing in phenomena related to DNA repair

Mukai

Sekiguchi²

2002

Oncogene

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DNA methylation is essential for embryonic development and important for transcriptional repression, as observed in several biological phenomena. These include genomic imprinting, X-inactivation and carcinogenesis. The basic mechanism by which DNA methlyation silences transcription is generally understood, but there is still much to be learned about how DNA methyltransferase is targeted to a specific region of the gene. Silencing by DNA methylation occurs at an early stage of carcinogenesis, when the DNA repair genes, MGMT and hMLH1, are frequently inactivated, resulting in mutations in key cancer-related genes in cells. Mice defective in Mgmt and/or Mlh1 gave clear evidence of the significant roles of these proteins in carcinogenesis.Recently, it has been demonstrated that DNA methylation is linked to histone methylation in fungi and plants, although it remains unknown whether this mechanism occurs in mammalian systems.

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“…Based on the phenotypic consequences of microdeletions affecting the PWS-SRO element of the IC, the AS-SRO element of the IC, or both, we have proposed that the maternal pattern of epigenetic modification, with CpG methylation of MKRN3, NDN and SNURF -SNRPN promoters and silencing of those genes, is the default state of the imprinted domain, that the PWS-SRO is unconditionally required for a chromosome to have the paternal pattern of epigenetic modification and gene expression, and that the AS-SRO is required for a chromosome to have the maternal pattern, if the chromosome has an intact PWS-SRO. 1 In other words, the PWS-SRO acts to activate the paternal copy of the imprinted domain or keep this copy active, 6 and the AS-SRO counteracts this activity.…”

Section: Introductionmentioning

confidence: 99%

Expression of SNURF–SNRPN upstream transcripts and epigenetic regulatory genes during human spermatogenesis

et al. 2009

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The imprinted domain in human 15q11-q13 is controlled by a bipartite imprinting centre (IC), which overlaps the 5 0 part of the paternally expressed SNURF -SNRPN gene. We have recently described two novel genes upstream of SNURF-SNRPN (PWRN1 and PWRN2), which are biallelically expressed in the testis. We have now found that PWRN1 represents an alternative 5 0 part of SNURF -SNRPN, and that its expression in the brain is imprinted. To determine when the locus is activated during spermatogenesis and which factors are involved in this process, we have mined gene-expression data of testicular biopsies from men with different types of spermatogenic failure. Whereas PWRN1-SNURF-SNRPN and PWRN2 are expressed in post-meiotic germ cells only, a hitherto undetected SNURF-SNRPN upstream transcript is expressed already at meiosis. Several epigenetic factors (eg, MBD1 and MBD2 isoforms, MBD3L1, SUVH39H2, BRDT, and EZH2) are upregulated at specific stages of spermatogenesis, suggesting that they play an important role in the epigenetic reprogramming during spermatogenesis.

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Maternal methylation imprints on human chromosome 15 are established during or after fertilization

Cited by 192 publications

References 20 publications

Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader–Willi syndromes

Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader–Willi syndromes

Gene silencing in phenomena related to DNA repair

Expression of SNURF–SNRPN upstream transcripts and epigenetic regulatory genes during human spermatogenesis

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