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. 2018 Feb 22;13(2):e0190698.
doi: 10.1371/journal.pone.0190698. eCollection 2018.

Offspring sex impacts DNA methylation and gene expression in placentae from women with diabetes during pregnancy

Jacqueline Alexander  1 , April M Teague  2   3 , Jing Chen  4 , Christopher E Aston  2 , Yuet-Kin Leung  4 , Steven Chernausek  2   3 , Rebecca A Simmons  5   6 , Sara E Pinney  1   6
Affiliations

Offspring sex impacts DNA methylation and gene expression in placentae from women with diabetes during pregnancy

Jacqueline Alexander et al. PLoS One. .

Abstract

Aims/hypothesis: We hypothesized that diabetes during pregnancy (DDP) alters genome-wide DNA methylation in placenta resulting in differentially methylated loci of metabolically relevant genes and downstream changes in RNA and protein expression.

Methods: We mapped genome-wide DNA methylation with the Infinium 450K Human Methylation Bead Chip in term fetal placentae from Native American and Hispanic women with DDP using a nested case-control design (n = 17 pairs). RNA expression and protein levels were assayed via RNA-Seq and Western Blot.

Results: Genome-wide DNA methylation analysis revealed 465 CpG sites with significant changes for male offspring, 247 for female offspring, and 277 for offspring of both sexes (p<0.001). Placentae from female offspring were 40% more likely to have significant gains in DNA methylation compared with placentae from male offspring exposed to DDP (p<0.001). Changes in DNA methylation corresponded to changes in RNA and protein levels for 6 genes: PIWIL3, CYBA, GSTM1, GSTM5, KCNE1 and NXN. Differential DNA methylation was detected at loci related to mitochondrial function, DNA repair, inflammation, oxidative stress.

Conclusions/interpretation: These findings begin to explain mechanisms responsible for the increased risk for obesity and type 2 diabetes in offspring of mothers with DDP.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Maternal and infant characteristics.
a) HgbA1C, b) Parity c) Gestational Age (weeks). *p<0.05. (n = 17 pairs).
Fig 2
Fig 2. CpG sites with significant changes in DNA methylation.
CpG sites with (a) AVDM > 10% and (b) AVDM > 15% and p<0.001. (a and b) Black indicates methylation increase in DDP. Gray region indicates methylation loss in DDP. (c) Genes with > 1 CpG site with significant change in DNA methylation (p<0.001).
Fig 3
Fig 3. Gene regulatory regions of probe sites included on the Infinium 450K Human Methylation Bead Chip.
TSS = Translational Start Site; UTR: Untranslated Region. a: Reference distribution of all probe sites included on the array. b, c and d: Distribution of probe site with AVDM > 10% and p< 0.001. b: All pairs c. Male offspring pairs. d. Female offspring pairs.
Fig 4
Fig 4. Differentially expressed genes in placenta exposed to DDP identified via RNA-Seq (n = 3 pairs per offspring sex).
Black represents differentially expressed transcripts with control > DDP; Gray represents DDP> control. a. Differentially expressed unique transcripts. b. Differentially expressed unique genes. RNA transcripts with expression sum >5, fold change>1.5, and p-value < 0.05.
Fig 5
Fig 5. Protein abundance for genes with changes in DNA methylation and mRNA expression.
a. PIWIL3 b. CYBA c. GSTM1 d. GSTM5 e. KCNE1 f. NXN; a–f: Protein abundance normalized to Actin or cofillin. a: All pairs (N = 14; 7 male pairs and 7 female pairs). b-d: Male offspring pairs (n = 7). e-f: Female offspring pairs (n = 7). * p<0.05; ** p<0.05.
See this image and copyright information in PMC

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