Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE et al.. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 40: 949-951

Division of Human Genetics, University of Southampton, Southampton SO16 6YD, UK.
Nature Genetics (Impact Factor: 29.35). 08/2008; 40(8):949-51. DOI: 10.1038/ng.187
Source: PubMed


We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57, which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.

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    • "Intriguingly, human ZFP57 functionally replaces mouse Zfp57 in embryonic stem cells and mutation in human ZFP57 affect DNA methylation at a subset of imprinted loci in individuals suffering transient neonatal diabetes (Mackay et al., 2008; Takikawa et al., 2013). Altogether these studies suggested a conserved role for Zfp57 in the maintenance of DNA methylation pattern at imprinted loci in mammals, despite clear differences in early embryonic developmental processes. "
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    ABSTRACT: DNA methylation in mammals is a key epigenetic modification essential to normal genome regulation and development. DNA methylation patterns are established during early embryonic development, and subsequently maintained during cell divisions. Yet, discrete site-specific de novo DNA methylation or DNA demethylation events play a fundamental role in a number of physiological and pathological contexts, leading to critical changes in the transcriptional status of genes such as differentiation, tumor suppressor or imprinted genes. How the DNA methylation machinery targets specific regions of the genome during early embryogenesis and in adult tissues remains poorly understood. Here, we report advances being made in the field with a particular emphasis on the implication of transcription factors in establishing and in editing DNA methylation profiles. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2015 · Journal of Cellular Physiology
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    • "However, STELLA's global binding and protection of the whole maternal genome from active demethylation makes it an unlikely candidate for DNA methylation maintenance at specific loci. ZFP57, a Krueppel-associated box (KRAB) domain zinc finger protein, has also been associated with imprinting maintenance (Fig. 4C; Li et al. 2008; Mackay et al. 2008). "
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    ABSTRACT: Methylation of DNA is an essential epigenetic control mechanism in mammals. During embryonic development, cells are directed toward their future lineages, and DNA methylation poses a fundamental epigenetic barrier that guides and restricts differentiation and prevents regression into an undifferentiated state. DNA methylation also plays an important role in sex chromosome dosage compensation, the repression of retrotransposons that threaten genome integrity, the maintenance of genome stability, and the coordinated expression of imprinted genes. However, DNA methylation marks must be globally removed to allow for sexual reproduction and the adoption of the specialized, hypomethylated epigenome of the primordial germ cell and the preimplantation embryo. Recent technological advances in genome-wide DNA methylation analysis and the functional description of novel enzymatic DNA demethylation pathways have provided significant insights into the molecular processes that prepare the mammalian embryo for normal development.
    Full-text · Article · Apr 2014 · Genes & development
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    • "Human maternal hypomethylation syndrome, in which LOM occurs at multiple maternal loci, is an imprinting disorder. DNMT3L and/or DNMT1 deletions were not detected but the ZFP57 mutation was detected in patients (41,42). Therefore, the effect of ZFP57 on DMRs during oocyte growth is key to functional imprinting. "
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    ABSTRACT: In mammals, genomic imprinting governed by DNA methyltransferase DNMT3A and its cofactor DNMT3L is essential for functional gametes. Oocyte-specific methylation imprints are established during oocyte growth concomitant with DNMT3A/DNMT3L expression, although the mechanisms of oocyte-specific imprinting are not fully understood. To determine whether the presence of DNMT3A/DNMT3L in oocytes is sufficient for acquisition of methylation imprints, we produced transgenic mice to induce DNMT3A/DNMT3L expression prematurely in oogenesis and analysed DNA methylation imprints. The results showed that two- to four-fold greater expression of DNMT3A/DNMT3L was achieved in non-growing oocytes versus fully grown oocytes derived from wild-type mice, but the analysed imprint domains were not methylated. Thus, the presence of DNMT3A/DNMT3L in non-growing oocytes is insufficient for methylation imprints and imprinted regions are resistant to DNMT3A/DNMT3L in non-growing oocytes. In contrast, excess DNMT3A/DNMT3L accelerated imprint acquisition at Igf2r, Lit1, Zac1, and Impact but not Snrpn and Mest in growing oocytes. Therefore, DNMT3A/DNMT3L quantity is an important factor for imprint acquisition. Transcription at imprinted domains is proposed to be involved in de novo methylation; however, transcription at Lit1, Snrpn, and Impact was observed in non-growing oocytes. Thus, transcription cannot induce DNMT3A catalysis at imprinted regions even if DNMT3A/DNMT3L is present. However, the accelerated methylation imprints in oocytes, with the exception of Igf2r, were erased during embryogenesis. In conclusion, a sufficient amount of DNMT3A/DNMT3L and a shift from the resistant to permissive state are essential to establish oocyte-specific methylation imprints and that maintenance of the acquired DNA methylation imprints is essential for functional imprinting.
    Full-text · Article · Mar 2014 · Human Molecular Genetics
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