miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor
NE Renthal, CC Chen, KC Williams… - Proceedings of the …, 2010 - National Acad Sciences
NE Renthal, CC Chen, KC Williams, RD Gerard, J Prange-Kiel, CR Mendelson
Proceedings of the National Academy of Sciences, 2010•National Acad SciencesThroughout most of pregnancy, uterine quiescence is maintained by increased
progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is
initiated/facilitated by a concerted series of biochemical events that activate inflammatory
pathways and have a negative impact on PR function. In this study, we uncovered a
previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as
hormonally modulated and conserved mediators of contraction-associated genes in the …
progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is
initiated/facilitated by a concerted series of biochemical events that activate inflammatory
pathways and have a negative impact on PR function. In this study, we uncovered a
previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as
hormonally modulated and conserved mediators of contraction-associated genes in the …
Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately down-regulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P4)/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction-associated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P4/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.
National Acad Sciences