Genomic imprinting disorders: lessons on how genome, epigenome and environment interact

Monk, Dave; Mackay, Deborah J G; Eggermann, Thomas; Maher, Eamonn R.; Riccio, Andrea

doi:10.1038/s41576-018-0092-0

Cited by 314 publications

(342 citation statements)

References 149 publications

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“…Enrichment of ERVs at SoC-CpGs is notable since most environment-sensitive mouse MEs are associated with IAPs (which are rodent-specific ERVs) 27 , and Krab zinc-finger protein (KZFP)-mediated repression of transposable elements (TEs) including ERVs has been proposed as a driver of the rapid evolution of gene regulation 38 . The KZFP ZFP57 is particularly interesting in this respect since its binding to DNA is linked both to repression of TEs and to the maintenance of genomic imprints in the pre-implantation embryo 20,39 . We previously identified a putative SoCassociated DMR in the ZFP57 promoter in blood from Gambian infants 22 , and a proximal CpG 21kbp from this DMR is in the set of discovery CpGs in this study, indicating a putative SoC association in Gambian 2 year-olds.…”

Section: Discussionmentioning

confidence: 99%

“…Our observation of increased sperm hypomethylation at SoC-associated loci, together with existing evidence that imprinted genes may be especially sensitive to prenatal exposures [20][21][22] , prompted us to investigate a potential link between SoC-sensitivity and parent-of-origin specific methylation (PofOm). A recent study used phased WGBS methylomes to identify regions of PofOm in 200 Icelanders 23 .…”

Section: Early Stage Embryo Gametic and Parent-of-origin Specific Mementioning

confidence: 99%

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Environmentally sensitive hotspots in the methylome of the early human embryo

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Saffari

Kessler

et al. 2019

Preprint

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In humans, DNA methylation marks inherited from sperm and egg are largely erased immediately following conception, prior to construction of the embryonic methylome. Exploiting a natural experiment of cyclical seasonal variation including changes in diet and nutritional status in rural Gambia, we replicated 134 loci with a common season-ofconception methylation signature in two independent child cohorts. These robust candidates for sensitivity to early environment were highly enriched for metastable epialleles, parent-of-origin specific methylation and regions hypomethylated in sperm. They tended to co-locate with endogenous retroviral (ERV1, ERVK) elements. Identified loci were influenced but not determined by measured genetic variation, notably through geneenvironment interactions. To the extent that early methylation changes impact gene expression, environmental sensitivity during genomic remethylation in the very early embryo could thus constitute a sense-record-adapt mechanism linking early environment to later phenotype. RESULTS Association of DNA methylation with Gambian season of conception

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Section: Discussionmentioning

confidence: 99%

Section: Early Stage Embryo Gametic and Parent-of-origin Specific Mementioning

confidence: 99%

Environmentally sensitive hotspots in the methylome of the early human embryo

Silver

Saffari

Kessler

et al. 2019

Preprint

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“…Similarly as for the H19 DMR-where epigenetic alterations that affect CTCF binding cause the growth-related imprinting disorders Beckwith-Wiedemann Syndrome (BWS) and Silver-Russell Syndrome (SRS) (2)-maternal CTCF binding at the Meg3 DMR is evolutionarily conserved in humans (5). Microdeletions and gains of methylation within this region have recently been linked to the developmental imprinting disorder Kagami-Ogata Syndrome (KOS14) (2,38), indicating that our observations are relevant to humans as well.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic imprinting is an epigenetic mechanism through which parental origin dictates monoallelic expression of about two hundred mammalian genes (1). Imprinting is essential for embryonic development, with diverse disease syndromes in humans attributed to loss of parental specificity (2). The majority of imprinted genes are clustered in about 20 chromosomal domains, where 'Imprinting Control Regions' (ICRs) dictate allele-specific gene activity.…”

Section: Introductionmentioning

confidence: 99%

CTCF controls imprinted gene activity at the mouseDlk1-Dio3andIgf2-H19domains by modulating allele-specific sub-TAD structure

Llères

Moindrot

Pathak

et al. 2019

Preprint

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Mammalian genomic imprinting is essential for development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. Here, we compared chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints-the Igf2-H19 and the Dlk1-Dio3 domains-and assessed the involvement of the insulator protein CTCF. At both domains, CTCF binds the maternal allele of a differentiallymethylated region (DMR), in addition to multiple instances of bi-allelic CTCF binding in their surrounding TAD (Topologically Associating Domain). On the paternal chromosome, bi-allelic CTCF binding alone is sufficient to structure a first level of sub-TAD organization. Maternal-specific CTCF binding at the DMRs adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal sub-TAD organisation. Genome-editing experiments at the Dlk1-Dio3 locus confirm that the maternal sub-TADs are essential during development to maintain the imprinted Dlk1 gene in an inactive state on the maternal chromosome.

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“…This may potentially lead to an up or down-regulation of the expression of alleles at that strand in a parent-of-origin-specific manner. There have been many approaches to capturing all genes that exhibit imprinting 71 . To identify more loci that are potentially involved in imprinting, a recent study analyzed combinations of DNA methylation and genotypes in the child of mother-child dyads 72 .…”

Section: Discussionmentioning

confidence: 99%

Gene-methylation interactions: Discovering region-wise DNA methylation levels that modify SNP-associated disease risk

Romanowska

Haaland

Jugessur

et al. 2019

Preprint

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The genetic code is tightly linked to epigenetic instructions as to what genes to express, and when and where to express them. The most studied epigenetic mark is DNA methylation at CpG dinucleotides. Today's technology enables a rapid assessment of DNA sequence and methylation levels at a single-site resolution for hundreds of thousands of sites in the human genome, in thousands of individuals at a time. Recent years have seen a rapid increase in epigenome-wide association studies (EWAS) searching for the causes of risk for genetic diseases that previous genome-wide association studies (GWAS) could not pinpoint. However, those single-omics data analyses led to even more questions and it has become clear that only by integrating data one can get closer to answers. Here, we propose two new methods within genetic association analyses that treat the level of DNA methylation at a given CpG site as environmental exposure. Our analyses search for statistical interactions between a given allele and DNA methylation (G×M e), and between a parent-of-origin effect and DNA methylation (PoO×Me). The new methods were implemented in the R package Haplin and were tested on a dataset comprising genotype data from mother-father-child triadsm with DNA methylation data from the children only. The phenotype here was orofacial clefts (OFC), a relatively common birth defect in humans, which is known to have a genetic origin and an environmental component possibly mediated by DNA methylation. We found no significant PoO×Me interactions and a few significant G×Me interactions. Our results show that the significance of these interaction effects depends on the genomic region in which the CpGs reside and on the number of strata of methylation level. We demonstrate that, by including the methylation level around the SNP in the analyses, the estimated relative risk of OFC can change significantly. We also discuss the importance of including control data in such analyses. The new methods will be of value for all the researchers who want to explore genome-and epigenome-wide datasets in an integrative manner. Moreover, thanks to the implementation in a popular R package, the methods are easily accessible and enable fast scans of the genome-and epigenome-wide datasets.

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Genomic imprinting disorders: lessons on how genome, epigenome and environment interact

Cited by 314 publications

References 149 publications

Environmentally sensitive hotspots in the methylome of the early human embryo

Environmentally sensitive hotspots in the methylome of the early human embryo

CTCF controls imprinted gene activity at the mouseDlk1-Dio3andIgf2-H19domains by modulating allele-specific sub-TAD structure

Gene-methylation interactions: Discovering region-wise DNA methylation levels that modify SNP-associated disease risk

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