Genome-wide DNA methylation and gene expression in human placentas derived from assisted reproductive technology

Area of Science:

• Reproductive biology
• Epigenetics
• Developmental biology

Background:

• Assisted reproductive technology (ART) is linked to adverse pregnancy outcomes, including growth disturbances and metabolic disorders.
• The molecular underpinnings of these ART-associated risks remain unclear, with ambiguity regarding their cause—ART procedures or subfertility.
• Investigating placental molecular changes is crucial for understanding ART's long-term effects.

Purpose of the Study:

• To elucidate the molecular mechanisms behind ART-associated placental alterations.
• To differentiate between effects caused by ART procedures and those stemming from underlying subfertility.
• To identify specific molecular pathways and genes affected in ART placentas.

Main Methods:

• Genome-wide DNA methylation analysis using EPIC Illumina microarrays.
• mRNA sequencing for gene expression profiling in placental tissues.
• Comparative analysis of placentas from ART, natural conception in subfertile couples, and intrauterine insemination.

Main Results:

• ART-associated placental changes were enriched in pathways related to hormonal regulation, insulin secretion, neuronal development, and vascularization.
• Reduced stromal cells and downregulated TRIM28 and NOTCH3 expression in ART placentas suggest impaired angiogenesis and growth.
• DNA methylation changes in imprinted regions and altered DLK1 expression were observed, linking ART and subfertility to imprinting defects.

Conclusions:

• Downregulation of TRIM28, NOTCH3, and DLK1 provides potential molecular explanations for ART-associated phenotypic features.
• Fresh embryo transfer was associated with more pronounced growth and metabolic changes compared to frozen embryo transfer.
• The observed molecular alterations in ART placentas also associate with subfertility, offering insights into the molecular basis of infertility.