Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface

Radek Bukowski*, Yoel Sadovsky, Hani Goodarzi, Heping Zhang, Joseph R. Biggio, Michael Varner, Samuel Parry, Feifei Xiao, Sean M. Esplin, William Andrews, George R. Saade, John V. Ilekis, Uma M. Reddy, Donald A. Baldwin, Stephanie Wilson Archer, Rachel L. Copper, Pamela B. Files, Stacy L. Harris, Ian Blair, Rita LeiteGalveston Margaret L. Zimmerle, Janet L. Brandon, Sonia Jordan, Angela Jones, Kelly Vorwaller, Sharon Quinn, Valerie S. Morby, Kathleen N. Jolley, Julie A. Postma, Kei Hoi Cheung, Donna DelBasso, Xiaobo Guo, Buqu Hu, Hao Huang, Lina Jin, Analisa L. Lin, Charles C. Lu, Laura Ment, Lauren Perley, Laura Jeanne Simone, Dwight J. Rouse, Donna Allard, Ronald Wapner, Michelle Divito, Sabine Bousleiman, Vilmarie Carmona, Rosely Alcon, Katty Saravia, Luiza Kalemi, Alan M. Peaceman, on behalf of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background. Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition. Methods. Samples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment (n = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). Enrolled were 35 pregnant women with four precisely and prospectively defined phenotypes: PL (n = 8), PNL (n = 10), TL (n = 7) and TNL (n = 10). Gene expression data were analyzed using shrunken centroid analysis to identify a minimal set of genes that uniquely characterizes each of the four phenotypes. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified each of the four phenotypes. The shrunken centroid analysis and 10 times 10-fold cross-validation was also used to minimize false positive finings and overfitting. Identified were the pathways and molecular processes associated with and the cis-regulatory elements in gene's 50 promoter or 30-UTR regions of the set of genes which expression uniquely characterized the four phenotypes. Results. The largest differences in gene expression among the four groups occurred at maternal fetal interface in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 50and 30 UTR regions. Conclusions. The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection.

Original languageEnglish (US)
Article number3685
JournalPeerJ
Volume2017
Issue number9
DOIs
StatePublished - 2017

Keywords

  • Gene expression
  • Labor
  • Pregnancy
  • Pretrem labor
  • Transcriptomics

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Bukowski, R., Sadovsky, Y., Goodarzi, H., Zhang, H., Biggio, J. R., Varner, M., Parry, S., Xiao, F., Esplin, S. M., Andrews, W., Saade, G. R., Ilekis, J. V., Reddy, U. M., Baldwin, D. A., Archer, S. W., Copper, R. L., Files, P. B., Harris, S. L., Blair, I., ... on behalf of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research (2017). Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface. PeerJ, 2017(9), [3685]. https://doi.org/10.7717/peerj.3685