Gene expression profiles based on maternal plasma cfDNA nucleosome footprints indicate fetal development and maternal immunity changes during pregnancy progress.

BACKGROUND: Pregnancy significantly alters the maternal immune system, affecting fetal development. The collection of tissues from the human placenta and fetus is not ethically or practically feasible at various gestational stages, thus limiting the study of gene expression in the fetus and placenta. Recent studies have shown that plasma cell-free DNA (cfDNA) nucleosome patterns can predict gene expression in the source tissue, offering insights into an individual's health status. This study aimed to identify pregnancy-related gene expression changes across gestational periods using cfDNA nucleosome distribution to understand fetal development and maternal immune changes.

METHODS: Plasma samples were collected from 150 healthy pregnant women in different trimesters (early, mid, and late) and 32 healthy nonpregnant women. The correlation between gene expression and physiological changes during pregnancy was evaluated by inferring differential expression profiles around the transcription start site (TSS) using cfDNA nucleosome distribution patterns obtained through whole-genome sequencing. We utilized Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to annotate differentially expressed genes with the mother and fetus.

RESULTS: We identified gene expression changes that support the regulation of fetal development and immune system function during pregnancy. Differential coverage genes were mainly enriched in pathways related to transcription and translation, organic compound metabolism, and immune regulation. In addition, differentially expressed genes with significant temporal trends were identified. Among them, the upregulated differential genes were mainly related to development, whereas those with downregulated trends were mainly related to the immune system response. This indicates that differential changes of the placenta and maternal are significantly correlated with the pregnancy status.

DISCUSSION: This study demonstrated the differential gene expression represented by the characteristic distribution of cfDNA nucleosome in maternal peripheral blood can effectively capture significant changes in maternal immunity and fetal development throughout pregnancy stages. It may help identify abnormal gene expression patterns associated with complications in pregnancy and childbirth, enhancing the quality of life and safety for both mother and fetus.