HoxA13 regulates phenotype regionalization of human pregnant myometrium

Abstract

Context: Bipedalism separates humans from most other animal species, but results in significant physiologic challenges, particularly with respect to the maintenance of pregnancy and induction of parturition.Acontracted lower uterine segment (LUS)anda relaxed uterine fundalmyometrium (FUN) during pregnancy are required to prevent pressure on the cervix from the fetal head due to gravity. With the onset of labor, this regionalization of myometrial function must be reversed, allowing descent of the fetus, dilation of the cervix, and expulsion of the fetus through the birth canal. However, the molecular mechanisms remain unclear. Objective and Design: This study sought to identify phenotypic regionalization of LUS and FUN during pregnancy, RNA sequencing was performed to analyze the human myometrial transcriptome. Real-time PCR and immunoblotting were applied to validate sequencing results. Cell contraction/ adhesion assays and gene microarrays were used to study the cellular functions of the identified genes. Results: Homeobox A13 (HoxA13), prostacyclin synthase (PTGIS), and periostin (POSTN) genes are more highly expressed in LUS than FUN of nonlaboring, but not laboring, myometrial cells at term. HoxA13 up-regulates transcription of PTGIS and POSTN genes. Elevated HoxA13 expression enhances myometrial cell contractility and cell- cell adhesion. Gene microarray studies show that HoxA13-regulated genes are associated with immune response, gap junction/cell adhesion, and pregnancy. Conclusion: The LUS expresses higher levels of HoxA13, PTGIS, and POSTN, and is more contractile than the FUN at term prior to labor. This pregnancy-maintaining regionalization of myometrial function may be mediated by HoxA13.