DNA-Methylation Profiling of Fetal Tissues Reveals Marked Epigenetic Differences between Chorionic and Amniotic Samples

Eckmann-Scholz, Christel; Bens, Susanne; Kolarova, Julia; Schneppenheim, Sina; Caliebe, Almuth; Heidemann, Simone; Kaisenberg, Constantin von; Kautza, Monika; Jonat, W.; Siebert, Reiner; Ammerpohl, Ole

doi:10.1371/journal.pone.0039014

Cited by 30 publications

(38 citation statements)

References 39 publications

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“…Earlier reports showed that hypermethylated promoters outnumbered hypomethylated promoters in DS chorionic villus samples and leukocytes [18], [27]. In our study, dominance of hypermethylation over hypomethylation in DS was seen in all genomic regions (promoters, intragenic regions, intergenic regions and transcription termination regions, Figure 2A–2F, Table S2), and in all autosomes (Figure 2G).…”

Section: Resultssupporting

confidence: 74%

“…We also compared our data with a published report using Illumina HumanMethylation27K BeadChip [18] and identified 2,894 CpGs that were analyzed by both data sets. Good correlation was observed for both normal (r = 0.929) and DS samples (r = 0.913) (Figure S2B–S2C).…”

Section: Resultsmentioning

confidence: 99%

“…Homocysteine metabolism is perturbed in children with DS, resulting in lower levels of SAM and S-adenosylhomocysteine (SAH) [14]. Small-scale DNA methylation analyses were performed to study potential DNA methylation perturbations in DS [15]–[18]. Intriguingly, promoter hypermethylation was observed in DS [18], despite of lower levels of SAM.…”

Section: Introductionmentioning

confidence: 99%

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Global DNA Hypermethylation in Down Syndrome Placenta

et al. 2013

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Down syndrome (DS), commonly caused by an extra copy of chromosome 21 (chr21), occurs in approximately one out of 700 live births. Precisely how an extra chr21 causes over 80 clinically defined phenotypes is not yet clear. Reduced representation bisulfite sequencing (RRBS) analysis at single base resolution revealed DNA hypermethylation in all autosomes in DS samples. We hypothesize that such global hypermethylation may be mediated by down-regulation of TET family genes involved in DNA demethylation, and down-regulation of REST/NRSF involved in transcriptional and epigenetic regulation. Genes located on chr21 were up-regulated by an average of 53% in DS compared to normal villi, while genes with promoter hypermethylation were modestly down-regulated. DNA methylation perturbation was conserved in DS placenta villi and in adult DS peripheral blood leukocytes, and enriched for genes known to be causally associated with DS phenotypes. Our data suggest that global epigenetic changes may occur early in development and contribute to DS phenotypes.

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Global DNA Hypermethylation in Down Syndrome Placenta

et al. 2013

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“…Little is known about epigenetic status in amniocytes. However, a recent study using array-based profiling determined that DNA-methylation levels in amniocytes are extremely high and many genes enriched with low CpG content are hypermethylated [68]. Linking highly expressed transcriptional repressors to specific epigenetic marks in amniocytes will deepen our understanding of their developmental potency.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis Reveals the Unique Stem Cell Identity of Human Amniocytes

et al. 2013

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Human amniotic fluid contains cells that potentially have important stem cell characteristics, yet the programs controlling their developmental potency are unclear. Here, we provide evidence that amniocytes derived from multiple patients are marked by heterogeneity and variability in expression levels of pluripotency markers. Clonal analysis from multiple patients indicates that amniocytes have large pools of self-renewing cells that have an inherent property to give rise to a distinct amniocyte phenotype with a heterogeneity of pluripotent markers. Significant to their therapeutic potential, genome-wide profiles are distinct at different gestational ages and times in culture, but do not differ between genders. Based on hierarchical clustering and differential expression analyses of the entire transcriptome, amniocytes express canonical regulators associated with pluripotency and stem cell repression. Their profiles are distinct from human embryonic stem cells (ESCs), induced-pluripotent stem cells (iPSCs), and newborn foreskin fibroblasts. Amniocytes have a complex molecular signature, coexpressing trophoblastic, ectodermal, mesodermal, and endodermal cell-type-specific regulators. In contrast to the current view of the ground state of stem cells, ESCs and iPSCs also express high levels of a wide range of cell-type-specific regulators. The coexpression of multilineage differentiation markers combined with the strong expression of a subset of ES cell repressors in amniocytes suggests that these cells have a distinct phenotype that is unlike any other known cell-type or lineage.

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“…[12][13][14][15] Nevertheless, placental tissue displays an intermediate distribution of methylation as compared, for example, with embryonal epithelial cells. 16,17 Moreover, there is greater epigenetic variation in extraembryonic than in embryonic tissue. 18 However, it is intriguing to postulate that in some children born small for gestational age (SGA) the underlying cause is a yet unrecognized imprinting disorder.…”

Section: Introductionmentioning

confidence: 99%

Frequency and characterization of DNA methylation defects in children born SGA

et al. 2012

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Various genes located at imprinted loci and regulated by epigenetic mechanisms are involved in the control of growth and differentiation. The broad phenotypic variability of imprinting disorders suggests that individuals with inborn errors of imprinting might remain undetected among patients born small for gestational age (SGA). We evaluated quantitative DNA methylation analysis at differentially methylated regions (DMRs) of 10 imprinted loci (PLAGL1, IGF2R DMR2, GRB10, H19 DMR, IGF2, MEG3, NDN, SNRPN, NESP, NESPAS) by bisulphite pyrosequencing in 98 patients born SGA and 50 controls. For IGF2R DMR2, methylation patterns of additional 47 parent pairs and one mother (95 individuals) of patients included in the SGA cohort were analyzed. In six out of 98 patients born SGA, we detected DNA methylation changes at single loci. In one child, the diagnosis of upd(14)mat syndrome owing to an epimutation of the MEG3 locus in 14q32 could be established. The remaining five patients showed hypomethylation at GRB10 (n ¼ 2), hypomethylation at the H19 3CTCF-binding site (n ¼ 1), hypermethylation at NDN (n ¼ 1) and hypermethylation at IGF2 (n ¼ 1). IGF2R DMR2 hypermethylation was detected in five patients, six parents of patients in the SGA cohort and two controls. We conclude that aberrant methylation at imprinted loci in children born SGA exists but seems to be rare if known imprinting syndromes are excluded. Further investigations on the physiological variations and the functional consequences of the detected aberrant methylation are necessary before final conclusions on the clinical impact can be drawn.

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DNA-Methylation Profiling of Fetal Tissues Reveals Marked Epigenetic Differences between Chorionic and Amniotic Samples

Cited by 30 publications

References 39 publications

Global DNA Hypermethylation in Down Syndrome Placenta

Global DNA Hypermethylation in Down Syndrome Placenta

Genome-Wide Analysis Reveals the Unique Stem Cell Identity of Human Amniocytes

Frequency and characterization of DNA methylation defects in children born SGA

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