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. 2017 Mar;9(3):267-278.
doi: 10.2217/epi-2016-0132. Epub 2017 Feb 17.

Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period

Elizabeth Martin  1 , Lisa Smeester  1 , Paige A Bommarito  1 , Matthew R Grace  2 , Kim Boggess  2 , Karl Kuban  3 , Margaret R Karagas  4 , Carmen J Marsit  5 , T Michael O'Shea  6 , Rebecca C Fry  1
Affiliations

Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period

Elizabeth Martin et al. Epigenomics. 2017 Mar.

Abstract

Aim: Sex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences.

Methods: Placental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort. The impact of gestational age on placental DNA methylation was further examined using the New Hampshire Birth Cohort Study for a total of n = 467 placentas.

Results: A total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10-7). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes.

Conclusion: These data highlight sex-dependent epigenetic patterning in the placenta and provide insight into differences in infant outcomes and responses to the perinatal environment.

Keywords: CpG DNA methylation; epigenetics; placenta; sexual dimorphism.

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Conflict of interest statement

Financial & competing interests disclosure

This research was supported by grants from the NIH including the Environmental Influences on Child Health Outcomes (ECHO) award (1U2COD023375, UG33OD023348 and 1UG3OD023275), the National Institute of Environmental Health Sciences (P42-ES007126, T32-ES007018, P42-ES007373, P01-ES022832) and the National Institute of Neurological Disorders and Stroke (5U01NS040069 and 2R01NS040069). Further support was provided by the Wake Forest School of Medicine Innovation Pilot Grant, the Harold M and Mary Earnhardt Eagle Endowed Fund for Pediatric and Neonatal Research, and the EPA (RD83544201). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Manhattan plot displaying all CpG probes tested for the analysis of sex-dependent DNA methylation in the placenta.
Probes are organized according to chromosomal positions. Probes in black and gray represent probes tested. Probes above the red line were those that were statistically significant. Probes in green are those that were validated in the replication cohort.
<b>Figure 2.</b>
Figure 2.. Heatmap displaying the 2745 validated sexually dimorphic probes.
Red represents increased methylation in males relative to females and blue represents decreased methylation in males relative to females. ELGAN: Extremely low gestational age newborn; UNC: University of North Carolina.
<b>Figure 3.</b>
Figure 3.. Comparison of sex-dependent beta differences between the extremely low gestational age newborns (X-axis) and University of North Carolina replication cohort (Y-axis) for all 2745 validated probes.
Autosomal probes are highlighted in gray, while those found on the X-chromosome are represented in black. ELGAN: Extremely low gestational age newborn; UNC: University of North Carolina.
<b>Figure 4.</b>
Figure 4.. Distribution of sex-dependent differential methylation by region for all probes.
(A) displays probe locations for overall, hypermethylated and hypomethylated autosomal probes. (B) displays probe locations for overall, hypermethylated and hypomethylated X-chromosome probes.
See this image and copyright information in PMC

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