Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57.
ABSTRACT 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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ABSTRACT: Genome-wide demethylation and remethylation of DNA during early embryogenesis is essential for development. Imprinted germline differentially methylated domains (gDMDs) established by sex-specific methylation in either male or female germ cells, must escape these dynamic changes and sustain precise inheritance of both methylated and unmethylated parental alleles. To identify other, gDMD-like sequences with the same epigenetic inheritance properties, we used a modified embryonic stem (ES) cell line that emulates the early embryonic demethylation and remethylation waves. Transient DNMT1 suppression revealed gDMD-like sequences requiring continuous DNMT1 activity to sustain a highly methylated state. Remethylation of these sequences was also compromised in vivo in a mouse model of transient DNMT1 loss in the preimplantation embryo. These novel regions, possessing heritable epigenetic features similar to imprinted-gDMDs are required for normal physiological and developmental processes and when disrupted are associated with disorders such as cancer and autism spectrum disorders. This study presents new perspectives on DNA methylation heritability during early embryo development that extend beyond conventional imprinted-gDMDs. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.Nucleic Acids Research 01/2015; 43(3). DOI:10.1093/nar/gku1386 · 8.81 Impact Factor
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ABSTRACT: Chronic inflammatory diseases, including allergies and asthma, are the result of complex gene-environment interactions. One of the most challenging questions in this regard relates to the biochemical mechanism of how exogenous environmental trigger factors modulate and modify gene expression, subsequently leading to the development of chronic inflammatory conditions. Epigenetics comprises the umbrella of biochemical reactions and mechanisms, such as DNA methylation and chromatin modifications on histones and other structures. Recently, several lifestyle and environmental factors have been investigated in terms of such biochemical interactions with the gene expression-regulating machinery: allergens; microbes and microbial compounds; dietary factors, including vitamin B12, folic acid, and fish oil; obesity; and stress. This article aims to update recent developments in this context with an emphasis on allergy and asthma research. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.Journal of Allergy and Clinical Immunology 01/2015; 135(1):15-24. DOI:10.1016/j.jaci.2014.11.009 · 11.25 Impact Factor
01/2014; 1(1):8. DOI:10.1186/2052-6687-1-8