Transient Neonatal Diabetes, ZFP57, and Hypomethylation of Multiple Imprinted Loci
Susanne E. BoonenDeborah MackayJohanne M D HahnemannLouise E DochertyKaren GrønskovAnna LehmannLise Grupe LarsenAndreas P. HaemersYves KockaertsLutgarde DoomsDũng Chí VũCấn Thị Bích NgọcPhuong Bich NguyenOlga KordonouriFrida SundbergPınar DayanıklıVijith PuthiCarlo L. AceriniAhmed F. MassoudZeynep TümerI. Karen Temple
58
Citation
38
Reference
10
Related Paper
Citation Trend
Abstract:
Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.There is yet no clear genotype-epigenotype-phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.Keywords:
Genomic Imprinting
Imprinting (psychology)
Transient (computer programming)
Genomic imprinting is an important regulatory mechanism that silences one of the parental copies of a gene. To systematically characterize this phenomenon, we analyze tissue specificity of imprinting from allelic expression data in 1582 primary tissue samples from 178 individuals from the Genotype-Tissue Expression (GTEx) project. We characterize imprinting in 42 genes, including both novel and previously identified genes. Tissue specificity of imprinting is widespread, and gender-specific effects are revealed in a small number of genes in muscle with stronger imprinting in males. IGF2 shows maternal expression in the brain instead of the canonical paternal expression elsewhere. Imprinting appears to have only a subtle impact on tissue-specific expression levels, with genes lacking a systematic expression difference between tissues with imprinted and biallelic expression. In summary, our systematic characterization of imprinting in adult tissues highlights variation in imprinting between genes, individuals, and tissues.
Imprinting (psychology)
Genomic Imprinting
Cite
Citations (213)
Imprinting (psychology)
Genomic Imprinting
Cite
Citations (72)
Genomic imprinting is a specialized transcriptional mechanism that results in the unequal expression of alleles based on their parent-of-origin. Many imprinted genes have been shown to be critical for proper embryonic and fetal development, and disruption of genomic imprinting at these loci has been associated with many development disorders. Recently, increased frequencies of many imprinting disorders have been correlated with the use of assisted reproductive technologies (ARTs). Rigorous and thorough testing of ARTs is required to determine their influence on processes of genomic imprinting. I hypothesize that the acquisition of genomic imprinting in developing germ cells is disrupted by superovulation, and that imprinting maintenance mechanisms are disrupted during early mouse development by culture media used in human ARTs. We have developed a method to evaluate the methylation and expression patterns of known imprinted genes from individual blastocysts. We utilized this technique to separately address the effects of two different hormone dosages, and six different culture media on imprinted methylation and expression. Superovulation resulted in a loss of imprinted methylation at both hormone concentrations tested, in a dose-dependent manner, and embryo culture resulted in a loss of imprinted methylation in all media tested. We conclude that both imprint acquisition and imprint maintenance can be perturbed by assisted reproductive technologies. Further analysis and use of our novel technique will allow more accurate and comprehensive study of the epigenetic effects of various environmental insults on the preimplantation embryo. (poster)
Genomic Imprinting
Imprinting (psychology)
Cite
Citations (0)
Background/Purpose: Genomic imprinting is a specialized transcriptional mechanism that results in the unequal expression of alleles based on their parent-of-origin [1]. Many imprinted genes are critical for proper embryonic and fetaldevelopment [2] and disruption of genomic imprinting are associated with many development disorders [3]. Recently, increased frequencies of imprinting disorders have been correlated with the use of assisted reproductive technologies (ARTs)[2]. Rigorous and thorough testing of ARTs is required to determine their influence on genomic imprinting and development. I hypothesize that imprinting maintenance mechanisms are disrupted during early mouse development by the environmental insult of culture media used in human ARTs, and that loss of imprinting correlates with delayed embryonic development. Methods: The specific aims of my project are to develop a method to evaluate the methylation and expression patterns of 4 known imprinted genes in individual blastocysts. Results: We have successfully developed a novel method to evaluate both imprinted methylation and expression from a single mouse blastocyst. This method has been tested and results compared to methods used to evaluate imprinted methylation and expression separately; we have determined that results obtained with a combined protocol are equivalent to either alone. I will use this method to evaluate relationships between development rates in culture andgenomic imprinting, as well as the effects of various culture media used formouse and human embryo culture on genomic imprinting. Conclusion: This analysis allow for a more comprehensive study ofthe effects of environmental insult on genomic imprinting and preimplantation embryo development. References: 1. Reik W, Walter J. Genomic imprinting:parental influence on the genome. Nat Rev Genet 2001;2:21-32. 2. Rodenhiser D, Mann M. Epigenetics andhuman disease: translating basic biology into clinical applications. CMAJ. 2006;174:341-8. 3.Paoloni-Giacobino A. Epigenetics in reproductive medicine. Pediatr Res 2007;61:51R-57R.
Genomic Imprinting
Imprinting (psychology)
Cite
Citations (0)
Abstract Genomic imprinting results in the biased expression of alleles depending on if the allele was inherited from the mother or the father. Despite the prevalence of sexual reproduction across eukaryotes, imprinting is only found in placental mammals, flowering plants, and some insects, suggesting independent evolutionary origins. Numerous hypotheses have been proposed to explain the selective pressures that favour the innovation of imprinted gene expression and each differs in their experimental support and predictions. Due to the lack of investigation of imprinting in land plants, other than angiosperms with triploid endosperm, we do not know whether imprinting occurs in species lacking endosperm and with embryos developing on maternal plants. Here, we discuss the potential for uncovering additional examples of imprinting in land plants and how these observations may provide additional support for one or more existing imprinting hypotheses.
Imprinting (psychology)
Genomic Imprinting
Sexual reproduction
Cite
Citations (16)
As a field of study, genomic imprinting has grown rapidly in the last 20 years, with a growing figure of around 100 imprinted genes known in the mouse and approximately 50 in the human. The imprinted expression of genes may be transient and highly tissue-specific, and there are potentially hundreds of other, as yet undiscovered, imprinted transcripts. The placenta is notable amongst mammalian organs for its high and prolific expression of imprinted genes. This review discusses the development of the human placenta and focuses on the function of imprinting in this organ. Imprinting is potentially a mechanism to balance parental resource allocation and it plays an important role in growth. The placenta, as the interface between mother and fetus, is central to prenatal growth control. The expression of genes subject to parental allelic expression bias has, over the years, been shown to be essential for the normal development and physiology of the placenta. In this review we also discuss the significance of genes that lack conservation of imprinting between mice and humans, genes whose imprinted expression is often placental-specific. Finally, we illustrate the importance of imprinting in the postnatal human in terms of several human imprinting disorders, with consideration of the brain as a key organ for imprinted gene expression after birth.
Imprinting (psychology)
Genomic Imprinting
Cite
Citations (231)
Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach.
Genomic Imprinting
Imprinting (psychology)
Cite
Citations (29)
Genomic imprinting (genetic imprinting) refers to parent of origin dependent gene expression. The presence of imprinted gene can cause cells with a full parental complement of functional autosomal genes to specifically express one allele but not the other, resulting in monoallelic expression of imprinted loci. Genomic imprinting is a normal process and has been found in primary animals and plants for a long time. Imprinted genes play a critical role in fetal growth and behavioral development even though they account for less than 5% of all human genes. Abnormal imprinting effects are associated with clinical disorders of overgrowth, undergrowth, mental retardation, or behavior abnormalities. In particular, loss of imprinting (LOI) is one of the most frequent genetic alterations in cancer. This review focused on genomic imprinting and disorders of genomic imprinting.
Genomic Imprinting
Imprinting (psychology)
Cite
Citations (0)
In plants, a subset of genes exhibit imprinting in endosperm tissue such that expression is primarily from the maternal or paternal allele. Imprinting may arise as a consequence of mechanisms for silencing of transposons during reproduction, and in some cases imprinted expression of particular genes may provide a selective advantage such that it is conserved across species. Separate mechanisms for the origin of imprinted expression patterns and maintenance of these patterns may result in substantial variation in the targets of imprinting in different species. Here we present deep sequencing of RNAs isolated from reciprocal crosses of four diverse maize genotypes, providing a comprehensive analysis of imprinting in maize that allows evaluation of imprinting at more than 95% of endosperm-expressed genes. We find that over 500 genes exhibit statistically significant parent-of-origin effects in maize endosperm tissue, but focused our analyses on a subset of these genes that had >90% expression from the maternal allele (69 genes) or from the paternal allele (108 genes) in at least one reciprocal cross. Over 10% of imprinted genes show evidence of allelic variation for imprinting. A comparison of imprinting in maize and rice reveals that only 13% of genes with syntenic orthologs in both species exhibit conserved imprinting. Genes that exhibit conserved imprinting in maize relative to rice have elevated dN/dS ratios compared to other imprinted genes, suggesting a history of more rapid evolution. Together, these data suggest that imprinting only has functional relevance at a subset of loci that currently exhibit imprinting in maize.
Imprinting (psychology)
Genomic Imprinting
Cite
Citations (0)
Preimplantation development is a period of dynamic epigenetic change that begins with remodeling of egg and sperm genomes, and ends with implantation. During this time, parental-specific imprinting marks are maintained to direct appropriate imprinted gene expression. We previously demonstrated that H19 imprinting could be lost during preimplantation development under certain culture conditions. To define the lability of genomic imprints during this dynamic period and to determine whether loss of imprinting continues at later stages of development, imprinted gene expression and methylation were examined after in vitro preimplantation culture. Following culture in Whitten's medium, the normally silent paternal H19 allele was aberrantly expressed and undermethylated. However, only a subset of individual cultured blastocysts (∼65%) exhibited biallelic expression, while others maintained imprinted H19 expression. Loss of H19 imprinting persisted in mid-gestation conceptuses. Placental tissues displayed activation of the normally silent allele for H19, Ascl2, Snrpn, Peg3 and Xist while in the embryo proper imprinted expression for the most part was preserved. Loss of imprinted expression was associated with a decrease in methylation at the H19 and Snrpn imprinting control regions. These results indicate that tissues of trophectoderm origin are unable to restore genomic imprints and suggest that mechanisms that safeguard imprinting might be more robust in the embryo than in the placenta.
Genomic Imprinting
Imprinting (psychology)
XIST
Cite
Citations (433)