Insights into imprinting from parent-of-origin phased methylomes and transcriptomes

Zink, Florian; Magnúsdóttir, Droplaug N; Magnússon, Ólafur Þ.; Walker, Nicolas; Morris, Tiffany; Sigurðsson, Ásgeir; Halldorsson, Gisli H.; Gudjonsson, Sigurjon A.; Melsted, Páll; Ingimundardóttir, Helga; Kristmundsdóttir, Snædís; Alexandersson, Kristjan F.; Helgadóttir, Anna; Guðmundsson, Jūlı́us; Rafnar, Thorunn; Jónsdóttir, Ingileif; Hólm, Hilma; Eyjolfsson, Gudmundur I.; Sigurðardóttir, Ólöf; Ólafsson, Ísleifur; Másson, Gísli; Guðbjartsson, Daníel F.; Þorsteinsdóttir, Unnur; Halldórsson, Bjarni V.; Stacey, Simon; Stefánsson, Kāri

doi:10.1038/s41588-018-0232-7

Cited by 107 publications

(195 citation statements)

References 52 publications

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“…This latter observation aligns with a growing body of evidence linking early environment, notably nutritional factors involved in one-carbon (C1) metabolism with methylation at imprinted regions 20,21 . Indeed we have previously noted an association between season of conception and several C1 metabolites at a maternally imprinted region at the small non-coding RNA VTRNA2-1 22 , consistent with evidence of 'polymorphic imprinting' linked to prenatal environment at this locus 23,37 . Furthermore, we previously found strong enrichment for proximal binding sites of several transcription factors (TFs) associated with the maintenance of PofOm in the early embryo at MEs 18 , although we were unable to replicate this at SoC-associated loci identified in this study.…”

Section: Discussionsupporting

confidence: 81%

“…We began by observing a very large enrichment for oocyte (maternally methylated) gDMRs, but not sperm gDMRs, at all PofOm loci identified by Zink et al 23 (Fig. 3D, right; Supplementary Table 8), confirming previous observations of an excess of PofOm loci that are methylated in oocytes only 23 . We found a particularly strong 122-fold enrichment for oocyte gDMRs (oo-gDMRs) persisting in placenta.…”

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

confidence: 85%

“…IGF1R signalling is implicated in fetal growth, glucose metabolism and cancer [46][47][48] , and DNAm differences at IGF1R have been observed in birthweight-discordant adult twins 49 . Another SoC-associated locus with PofOm is approximately 300kbp from the 14q32 DLK1-MEG3 imprinted region, close to the imprinted C14MC microRNA cluster 50 , and within 80kb of a region with PofO-ASE 23 . Epigenetic and transcriptional changes at several C14MC microRNAs have been implicated in cancer [51][52][53] , and genetic and epigenetic mutations in the 14q32 region are linked to imprinting disorders including Temple syndrome 54,55 .…”

Section: Discussionmentioning

confidence: 99%

“…Regions of PofOm detected in postnatal samples tend to be differentially methylated in gametes 23 , and may thus have evaded the widespread epigenetic reprogramming that occurs in the pre-implantation embryo 24 . We tested this directly by interrogating data from a wholegenome screen for germline differentially methylated regions (gDMRs) that persist to the blastocyst stage and beyond 25 .…”

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

Silver

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: Discussionsupporting

confidence: 81%

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

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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

confidence: 99%

See 2 more Smart Citations

Environmentally sensitive hotspots in the methylome of the early human embryo

Silver

Saffari

Kessler

et al. 2019

Preprint

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“…35 However, imprinted genes typically have key functions in growth and development, 10 as seen by the fact that patients with imprinting disorders often present with intellectual disability and growth abnormalities. The proportion of human genes that undergo imprinting is small (about 0.5%), although some may have yet to be discovered.…”

Section: Genomic Imprintingmentioning

confidence: 99%

Clinical epigenetics: a primer for the practitioner

Aygün

Björnsson

2019

Develop Med Child Neuro

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ARTAssistive reproductive technology BWSBeckwith-Wiedemann syndrome MLIDMulti-locus imprinting disorder PWS Prader-Willi syndrome SRS Silver-Russell syndrome TND Transient neonatal diabetes Disruption of epigenetic modifications and the factors that maintain these modifications is rapidly emerging as a cause of developmental disorders. Here we summarize some of the major principles of epigenetics including how epigenetic modifications are: (1) normally reset in the germ line, (2) form an additional layer of interindividual variation, (3) are environmentally sensitive, and (4) change over time in humans. We also briefly discuss the disruption of growth and intellect associated with the Mendelian disorders of the epigenetic machinery and the classical imprinting disorders (such as Beckwith-Wiedemann syndrome, Silver-Russell syndrome, Prader-Willi syndrome, and Angelman syndrome), as well as suggesting some diagnostic considerations for the clinicians taking care of these patients. Finally, we discuss novel therapeutic strategies targeting epigenetic modifications, which may offer a safe alternative to up and coming genome editing strategies for the treatment of genetic diseases. This review provides a starting point for clinicians interested in epigenetics and the role epigenetic disruption plays in human disease.

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Alteration of methylation status in archival DNA samples: A qualitative assessment by methylation specific polymerase chain reaction

Iyer

Hasan

2020

Environ and Mol Mutagen

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DNA methylation is an epigenetic mechanism that regulates gene expression, which also facilitates genomic imprinting. Genomic imprinting is responsible for differential expression of genes based on parent of origin. Altered methylation of parental alleles results in imprinting disorders diagnosed by methylation specific polymerase chain reaction (MS-PCR) technique. With increasing evidence of genes under epigenetic influence, methylation studies are extensively performed on archival samples. To evaluate effect of storage and storage conditions on DNA methylation, a systematic MS-PCR based analysis was planned on an imprinted gene, SNRPN, located on chromosome 15q11.2. It was assessed by MS-PCR on fresh, 4 −20, and −80 C stored DNA samples for different time periods for systematic evaluation of methylation status. Technical factors like type of sample processing, method of DNA isolation, primer region polymorphism, sample heterogeneity were also evaluated. DNA methylation was observed to be altered for SNRPN gene after storage at −80 C from 2 months onwards. Long-term storage of DNA at −80 C results in altered DNA methylation status. This may lead to false MS-PCR diagnosis of imprinting disorders. Our proof of concept study should be followed with quantitative validation since the findings have critical implications in the present era of biobanking.

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Insights into imprinting from parent-of-origin phased methylomes and transcriptomes

Cited by 107 publications

References 52 publications

Environmentally sensitive hotspots in the methylome of the early human embryo

Environmentally sensitive hotspots in the methylome of the early human embryo

Clinical epigenetics: a primer for the practitioner

Alteration of methylation status in archival DNA samples: A qualitative assessment by methylation specific polymerase chain reaction

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