Sex-influenced DNA methylation differs by placental cell type.

Area of Science:

• Reproductive Biology
• Epigenetics
• Genomics

Background:

• Sex differences in human placenta function and morphology impact pregnancy outcomes.
• X chromosome inactivation (XCI) is key for dosage compensation but shows low X-chromosome promoter DNA methylation (DNAme) in the placenta.
• Placental cell-type-specific sex differences in DNAme remain uninvestigated.

Purpose of the Study:

• To investigate sex-influenced DNA methylation (DNAme) differences across distinct placental cell types.
• To determine if DNAme patterns align with cellular developmental origins and sex chromosome complement.

Main Methods:

• Analyzed DNAme in sorted endothelial, stromal, cytotrophoblast, and Hofbauer cells from term placentas using Illumina arrays.
• Compared placental cell DNAme with data from chorionic plate and umbilical cord endothelial cells.
• Conducted sex-stratified analyses of X/Y and autosomal DNAme to identify sex chromosome-associated differences.

Main Results:

• DNA methylation distribution on X and Y chromosomes varied significantly by cell type.
• Differences in DNAme clustered according to developmental origins: extraembryonic mesoderm (endothelial/stromal), trophectoderm (cytotrophoblast), and epiblast (Hofbauer cells).
• XCI-associated DNAme was absent in endothelial/stromal cells and low in trophoblasts, suggesting cell-type-specific de novo DNAme establishment.

Conclusions:

• Lack of X-linked promoter DNAme in endothelial/stromal cells reflects their distinct developmental origin.
• Autosomal DNAme differences correlated with cell relationships and sex chromosome complement.
• Sex chromosome effects on pregnancy outcomes likely vary depending on placental cell type.