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The Role of Placental DNA Methylation in the Pathogenesis of Chronic Intervillositis of Unknown Etiology

ABSTRACT: Objectives: Chronic intervillositis of unknown etiology (CIUE) is the pathological influx of maternal inflammatory cells into the intervillous space of the placenta without demonstrable cause. CIUE is associated with placental damage and increased risk of pregnancy loss, fetal demise, and growth restriction. The pathogenic mechanism is unclear, and we lack biomarkers for detection, and treatments to prevent recurrence. DNA methylation (DNAme) is a biomarker altered in association with many disease states. We hypothesized that CIUE may be associated with a distinct signature placental DNAme signature. Methods: DNAme was profiled using the Illumina Infinium MethylationEPIC v2.0 array on fresh-frozen placental tissue. After quality control, data were available for 24 CIUE (14 high grade, 10 low grade) and 27 non-CIUE placental samples, plus six independent decidua samples. CIUE was confirmed and graded by a perinatal pathologist. Contamination was assessed using the 65 array genotyping probes, placental cell composition and epigenetic age were estimated. After processing, DNAme data were available at 855,732 CpGs. Results: Several lines of evidence indicated maternal DNA in CIUE placentas. Genetic contamination metrics were higher in CIUE than non-CIUE cases. In XY samples, X chromosome copy number increased with CIUE grade, suggesting XX contaminating DNA. Principal components analysis placed CIUE samples closer to decidua along PC1 than non-CIUE samples, cell composition showed elevated Hofbauer cells, monocytes, and neutrophils in CIUE. Epigenetic age was higher in CIUE versus non-CIUE samples. Together, these findings suggested an increased concentration of non-self XX DNA in CIUE cases, likely originating from an adult, macrophage-rich source, suggesting a maternal origin. An epigenome-wide association study found that all significant differentially methylated loci associated with CIUE were attenuated after adjusting for cell composition. Conclusions: Our results illustrate that placental DNAme patterns in CIUE reflect signatures of maternal infiltration rather than intrinsic DNAme alterations. This study also highlights the value of integrating the diverse molecular data outputs of DNAme arrays to explore the presence of maternal cells in placental tissue. *************************************************************** IDAT files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable SNP genotyping data for open access but are available upon reasonable request to JT or WPR for research use. ***************************************************************

ORGANISM(S): Homo sapiens

PROVIDER: GSE307664 | GEO | 2025/12/30

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE307664_processed_betas.csv.gz	Csv
	GSE307664_raw_methunmeth.csv.gz	Csv

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Project description:The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion that results in an environment with high resistance to blood flow, decreased availability of nutrients to the placenta, and increased hypoxia. Despite accumulating knowledge linking inadequate trophoblast invasion with placental insufficiency and FGR, current treatment options are limited to iatrogenic delivery, usually preterm. We have developed a non-viral, polymer-based nanoparticle that facilitates transient human insulin-like 1 growth factor (hIGF1) gene delivery specifically to placental trophoblast. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the sub-placenta/decidua that will provide insight into the underlying mechanism driving FGR, and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pig dams underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. Histological assessment of the sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast in the MNR sub-placenta/decidua which was associated with downregulation of genes involved in epithelium development and the regulation of cell migration. hIGF1 nanoparticle treatment results in marked changes to transporter activity in the MNR + hIGF1 sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment in Control + hIGF1 sub-placenta/decidua was associated with downregulation of kinase signaling and increased proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and that contribute to placental insufficiency. Additionally, this study has increased our understanding of pathways that hIGF1 nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.

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The Role of Placental DNA Methylation in the Pathogenesis of Chronic Intervillositis of Unknown Etiology

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