Abstract
BackgroundHuman placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Here, we present an analysis of sex differences in autosomal DNAme in the uncomplicated term placenta (n = 343) using the Illumina 450K array.ResultsAt a false discovery rate < 0.05 and a mean sex difference in DNAme beta value of > 0.10, we identified 162 autosomal CpG sites that were differentially methylated by sex and replicated in an independent cohort of samples (n = 293). Several of these differentially methylated CpG sites were part of larger correlated regions of sex differential DNAme. Although global DNAme levels did not differ by sex, the majority of significantly differentially methylated CpGs were more highly methylated in male placentae, the opposite of what is seen in differential methylation analyses of somatic tissues. Patterns of autosomal DNAme at these 162 CpGs were significantly associated with maternal age (in males) and newborn birthweight standard deviation (in females).ConclusionsOur results provide a comprehensive analysis of sex differences in autosomal DNAme in the term human placenta. We report a list of high-confidence autosomal sex-associated differentially methylated CpGs and identify several key features of these loci that suggest their relevance to sex differences observed in normative and complicated pregnancies.
Highlights
Placental DNA methylation (DNAme) data are a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation
Genome-wide measures of DNAme do not differ by placental sex To investigate whether female (XX) and male (XY) term placentae had different global DNAme profiles, we evaluated mean genome-wide DNAme at all autosomal Cytosine-guanine dinucleotide (CpG) (n = 324,104) and at repetitive elements, frequently interrogated as surrogates for global DNAme as they comprise roughly 30% of all genomic nucleotides and 30% of CpG dinucleotides, [59]
The most differentially methylated CpG sites are annotated with associated genes names. c The number of differentially methylated (FDR < 0.05) CpG sites at various Δβ thresholds; Differentially methylated position (DMP) that are more highly methylated in male samples are indicated in red, and DMPs more highly methylated in female samples are indicated in orange. d Percentage of DMPs at various Δβ thresholds that replicate (FDR < 0.05, Δβ same direction) in GSE71678, colored by sex with higher DNAme. e For all DMPs at the Δβ thresholds considered, the percentage of DMPs with higher male DNAme
Summary
Human placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Sex differences during prenatal development are likely affected by sex differences in the placenta, the organ critical for regulating growth and development of the embryo/fetus throughout gestation. Placental cells harbor the same sex chromosome complement as the fetus, and sex differences in placental function, for example placental response to infection and stress, could contribute to sex differences in fetal growth and development [5, 7, 8]. Placental DNA methylation (DNAme) data are a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation
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