Differential Timing in Activation of Contraction-Associated Genes in Myometrium of Pregnant Mice with Preterm Labor Induction Suggests Distinct Epigenetic Mechanisms
Presentation Number: SUN-0036
Date of Presentation: June 22nd, 2014
Alina Peraza Montalbano*1 and Carole R Mendelson2
1UT Southwestern Med Cntr, Dallas, TX, 2Univ Texas Southwestern Med Ctr, Dallas, TX
Preterm birth is the leading cause of neonatal morbidity and mortality in developed countries and the second leading cause of death in children under the age of 5 yr worldwide. While ~30% of preterm labor is due to underlying infection, the majority of cases are of unknown etiology. Notably, both term and preterm labor are associated with increased levels of proinflammatory mediators (e.g. interleukin-1β (IL-1β), interleukin-6 (IL-6)), within fetal and maternal reproductive tissues, which activate inflammatory transcription factors (NF-κB, AP-1) and expression of genes encoding contraction-associated proteins (CAP) (e.g. oxytocin receptor (OXTR), connexin-43 (CX43), cyclooxygenase 2 (COX-2)). By contrast, uterine quiescence throughout most of pregnancy is maintained by increased circulating progesterone (P4) and enhanced progesterone receptor (PR) transcriptional activity, which silence expression of CAP genes and proinflammatory mediators. We propose that increased P4/PR inhibits CAP gene expression, in part, by blocking activation and DNA-binding of inflammatory transcription factors and by causing repressive changes in chromatin structure. The objective of this study was to define the epigenetic regulation of CAP genes during pregnancy and effects of P4 withdrawal, leading to preterm labor. Timed-pregnant ICR/CD1 mice at 16.5 days post-coitum (dpc) (19 dpc=term) were given a single injection of the PR antagonist, RU486, or vehicle; myometrial tissues were isolated 1 h, 3 h, and 8 h post-injection and during preterm labor. Using RT-qPCR, we observed that RU486 caused a rapid induction of OXTR (p=0.005) and CX43 (p=0.005) mRNA in myometrium, compared to vehicle-injected mice; this was evident within 3 h of treatment and sustained through labor initiation, 12-14 h after treatment. By contrast, IL-1β, IL-6 and TNF-α mRNA levels were significantly upregulated only 8 h (p=0.05) after RU486 injection, while COX-2 mRNA failed to increase until preterm labor occurred. Because the kinetics of activation of CAP genes in response to P4/PR withdrawal is mediated by transcription factor binding and collective histone modifications at their promoters, we suggest that the mechanisms for activation of IL-1β, and COX-2 genes differ markedly from OXTR and CX43 at the levels of transcription factor recruitment and chromatin modification. Analysis of the underlying epigenetic mechanisms will provide much needed insight into the pathogenesis of preterm birth.
Nothing to Disclose: APM, CRM