Genome-wide DNA methylation, imprinting, and gene expression in human placentas derived from Assisted Reproductive Technology

Abstract

Assisted reproductive technology (ART) has been associated with increased risk for growth disturbance and imprinting disorders, but the molecular mechanisms and whether they are a result of the ART procedures or the underlying subfertility are unknown. Here we performed genome-wide DNA methylation analysis by EPIC Illumina microarrays and gene expression analysis by mRNA sequencing for a total of 80 ART and 77 control placentas, including separate procedure- and sex-specific analyses. ART-associated changes enriched in the pathways of hormonal regulation, insulin resistance, neuronal development, and vascularization. Observed changes in the number of stromal cells as well as TRIM28 and NOTCH3 expressions in ART placentas indicated impaired angiogenesis and growth. The enrichment of DNA methylation changes in the imprinted regions and alterations in TRIM28, ZFP57, and NLRP5 suggested defective stabilization of the imprinting. Furthermore, downregulated expression of imprinted endocrine signaling molecule DLK1, associated with both ART and subfertility, provides a potential mechanism for the metabolic and phenotypic features associated with ART.