Abstract
BackgroundPreterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data.MethodsMyometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data.ResultsWe identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse.ConclusionsLabor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human “functional progesterone withdrawal.” This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0632-4) contains supplementary material, which is available to authorized users.
Highlights
Preterm birth is recognized as the primary cause of infant mortality worldwide
Myometrial transcriptome modeling of term and preterm labor induced by progesterone withdrawal or inflammation Using RNA sequencing (RNA-Seq) we undertook temporal transcriptome profiling on mouse myometrial samples collected across a time series from animals experiencing spontaneous term labor, or PTL following pharmacologically induced (RU486) progesterone withdrawal, or inflammation-induced (LPS) PTL (Fig. 1a)
Principal component analysis (PCA) of myometrial transcriptome data revealed that both spontaneous term labor and PTL following progesterone withdrawal involve similar trajectories of transcriptome changes preceding labor
Summary
Preterm birth is recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; the relative contribution of each remains unclear. We have recently shown that uterine activation of the inflammatory transcription factor activator protein 1 (AP-1), and not NFkB, is sufficient to stimulate inflammatory and contractile gene transcription and pathways causing PTL in the mouse at gestation day 16, when circulating progesterone levels are high [11,12,13] While these findings indicate that pathophysiological PTL and spontaneous term labor in the mouse involve modulation of different hormonal and inflammatory pathways, their convergence in a common contractile phenotype suggests overlap and redundancy in the underlying mechanisms of parturition
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