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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 6

Steroids alter neuronal developmental pathways in vivo.

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Steroids alter neuronal developmental pathways in vivo.
(A) Comparison o...
(A) Comparison of gene set enrichment results for each steroid treatment regimen in hippocampus 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). (B–D) Heatmaps of gene set enrichments in the hippocampus for each steroid treatment regimen or term versus preterm controls, to clarify maturation, common treatment, or specific regimen impacts for (B) GO terms, (C) single-cell biomarkers, or (D) curated pathways. Full differential expression gene sets P value ordered (signed according to the fold direction) are provided for all GSEA analyses. Heatmap color coding uses GSEA normalized enrichment score, with red indicating positive and blue indicating negative enrichment. n = 47 animals for lung, 35 animals for amniotic fluid, and 46 animals for hippocampus. (E) Gene expression box plots for selected genes illustrating the range of intratreatment variation among hippocampal transcripts induced by the different steroid regimens. Selected genes are from the set of n = 38 genes with log2 fold change < –0.4 and an unadjusted P < 0.05 in the comparison of combined steroid treatment samples to preterm controls.

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