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Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques
Augusto F. Schmidt, Daniel J. Schnell, Kenneth P. Eaton, Kashish Chetal, Paranthaman S. Kannan, Lisa A. Miller, Claire A. Chougnet, Daniel T. Swarr, Alan H. Jobe, Nathan Salomonis, Beena D. Kamath-Rayne
Augusto F. Schmidt, Daniel J. Schnell, Kenneth P. Eaton, Kashish Chetal, Paranthaman S. Kannan, Lisa A. Miller, Claire A. Chougnet, Daniel T. Swarr, Alan H. Jobe, Nathan Salomonis, Beena D. Kamath-Rayne
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Research Article Reproductive biology

Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques

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Abstract

Accurate estimate of fetal maturity could provide individualized guidance for delivery of complicated pregnancies. However, current methods are invasive, have low accuracy, and are limited to fetal lung maturation. To identify diagnostic gestational biomarkers, we performed transcriptomic profiling of lung and brain, as well as cell-free RNA from amniotic fluid of preterm and term rhesus macaque fetuses. These data identify potentially new and prior-associated gestational age differences in distinct lung and neuronal cell populations when compared with existing single-cell and bulk RNA-Seq data. Comparative analyses found hundreds of genes coincidently induced in lung and amniotic fluid, along with dozens in brain and amniotic fluid. These data enable creation of computational models that accurately predict lung compliance from amniotic fluid and lung transcriptome of preterm fetuses treated with antenatal corticosteroids. Importantly, antenatal steroids induced off-target gene expression changes in the brain, impinging upon synaptic transmission and neuronal and glial maturation, as this could have long-term consequences on brain development. Cell-free RNA in amniotic fluid may provide a substrate of global fetal maturation markers for personalized management of at-risk pregnancies.

Authors

Augusto F. Schmidt, Daniel J. Schnell, Kenneth P. Eaton, Kashish Chetal, Paranthaman S. Kannan, Lisa A. Miller, Claire A. Chougnet, Daniel T. Swarr, Alan H. Jobe, Nathan Salomonis, Beena D. Kamath-Rayne

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Figure 5

Treatment-specific and common pathways impacted in rhesus lung and amniotic fluid.

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Treatment-specific and common pathways impacted in rhesus lung and amnio...
(A and B) Comparison of gene set enrichment results for each steroid treatment regimen in (A) lungs or (B) amniotic fluid relative to term versus preterm impacted genes (up- or downregulated), to identify consistent maturation impacts. Top 500 up- and downregulated genes for each signature were used for GSEA. The filled triangulates indicate P < 0.1 (FDR corrected). (C and D) Heatmaps of gene set enrichments for each steroid treatment regimen or term versus preterm controls, to clarify maturation, common treatment or specific regimen impacts for GO terms or cellular biomarkers (AltAnalyze). (C) Heatmaps for lung. (D) Heatmaps for amniotic fluid. Full differential expression gene sets P value ordered (signed according to the fold direction) are provided for all fgsea analyses. Heatmap color coding uses fgsea normalized enrichment score, with red indicating positive and blue indicating negative enrichment. n = 47 animals for lung and 35 animals for amniotic fluid. (E) Box plots common upregulated genes in fetal lung and amniotic fluid comparing corticosteroid treated versus preterm controls. Open circles denote individual biological replicates lung (FC ≥ 1.5, unadjusted P < 0.05) and amniotic fluid (log[FC] > 0, unadjusted P < 0.05).

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