Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics

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.

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

“…We collected the 101 abstracts and after analysing them, we found that most studies focused on preeclampsia, placental villi tissue, and animal models or maternal or cord blood. Six studies used RNAseq; two focused in cord blood [20,21], two on animal models [22,23] and two on the transcriptome of normal labor [12,24].…”

“…It has been proposed than pregnancy is maintained by down-regulation of chemokines at the maternal-fetal interface [25]. Removal of the down-regulation results in term birth while in the case of PTB, the activation of multiple pathways of the immune system overrides this down-regulation [3,22,25,27–30]. In concordance with this idea, we found that up-regulated genes were mostly related to immune response (e.g.…”

“…Obtained reads were trimmed and clipped for quality control in Trimmomatic v0.32 [17], and checked for quality using FastQC v0.11.2 [21]. Reads were then aligned to the GRCh37 reference genome using Tophat v2.1.0 [22] and Ensembl annotations [23], as derived from Ensembl Release 75.…”

Cervical gene delivery of the antimicrobial peptide, Human β-defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth

“…Following bacterial administration, mice were placed in individual cages and continuously monitored with individual closed-circuit television cameras and a digital video recorder 68 . Time to delivery was recorded and defined as the number of hours from the time of bacterial administration to delivery of the first pup.…”

Cervical Gene Delivery of the Antimicrobial Peptide, Human β-Defensin (HBD)-3, in a Mouse Model of Ascending Infection-Related Preterm Birth

“…Following bacterial administration, mice were placed in individual cages and continuously monitored with individual closed-circuit television cameras and a digital video recorder (29). Time to delivery was recorded and defined as the number of hours from the time of bacterial administration to delivery of the first pup.…”