H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition
Patrice Nancy, Johan Siewiera, Gabrielle Rizzuto, Elisa Tagliani, Ivan Osokine, Priyanka Manandhar, Igor Dolgalev, Caterina Clementi, Aristotelis Tsirigos, Adrian Erlebacher
Patrice Nancy, Johan Siewiera, Gabrielle Rizzuto, Elisa Tagliani, Ivan Osokine, Priyanka Manandhar, Igor Dolgalev, Caterina Clementi, Aristotelis Tsirigos, Adrian Erlebacher
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Research Article Reproductive biology

H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition

Abstract

Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a noncontractile state until term and then surmounts this state to enter labor. Here, we show that dynamic generation and erasure of the repressive histone modification tri-methyl histone H3 lysine 27 (H3K27me3) in decidual stromal cells dictate both elements of pregnancy success in mice. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets ensured uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and most unexpectedly, generating myofibroblasts and associated wound-healing responses. In late gestation, genome-wide H3K27 demethylation allowed for target gene upregulation, decidual activation, and labor entry. Pharmacological inhibition of H3K27 demethylation in late gestation not only prevented term parturition, but also inhibited delivery while maintaining pup viability in a noninflammatory model of preterm parturition. Immunofluorescence analysis of human specimens suggested that similar regulatory events might occur in the human decidua. Together, these results reveal the centrality of regulated gene silencing in the uterine adaptation to pregnancy and suggest new areas in the study and treatment of pregnancy disorders.

Authors

Patrice Nancy, Johan Siewiera, Gabrielle Rizzuto, Elisa Tagliani, Ivan Osokine, Priyanka Manandhar, Igor Dolgalev, Caterina Clementi, Aristotelis Tsirigos, Adrian Erlebacher

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Figure 5

Effect of GSK-J4 on late-gestation pregnancy and parturition.

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Effect of GSK-J4 on late-gestation pregnancy and parturition. Mice were ...
Mice were injected daily with GSK-J4 or vehicle starting on E13.5. (A) qRT-PCR analysis of mRNA expression in dissected decidual and myometrial tissue layers on E17.5, with log2(fold change) between GSK-J4– and vehicle-treated mice displayed on volcano plots (n = 6 mice/group). Genes affected by GSK-J4 (P < 0.05) are indicated. Supplemental Figure 7, A–C, shows individual gene-expression levels; the unmarked genes encode epigenetic modifiers, tissue layer–specific markers, and Pgr. The symbol key lists mean log2(fold change) ± SD for each group and the P value of its comparison to 0.00 by 1-sample t test. Groups were compared with each other by 1-way ANOVA (P < 0.0001) followed by Sidak’s multiple comparison test (P values shown in each plot). (B) Effects of GSK-J4 and P4 on delivery time (n = 8 mice/group); P values were determined by the log-rank (Mantel-Cox) test. (C) Effect of GSK-J4 on dinoprost-induced preterm delivery. Mice were injected with dinoprost and/or P4 on E16.5. Representative images from 6–8 mice/group. Injection of E16.5 pregnant mice with dinoprost unfailingly induced delivery within 24 hours (0/7 mice remained pregnant), 1 day before term. None of the delivered pups were viable. While P4 cotreatment prevented early delivery in all cases (6/6), only 27% of the fetuses were viable. Arrows indicate 2 pale, dead fetuses. In contrast, GSK-J4 cotreatment both prevented delivery (7/7 mice pregnant; P = 0.0006 compared with dinoprost alone, Fisher’s exact test) and maintained pup viability (86%; P < 0.0001 compared with dinoprost plus P4, Fisher’s exact test). Asterisks indicate implantation sites that had resorbed earlier in gestation. (D) Plasma P4 levels (mean ± SEM; n = 3 mice/group). GSK-J4/dinoprost–treated mice had low plasma P4 (P < 0.0001, 1-way ANOVA; *P < 0.0001) and thus had undergone luteolysis; presumably, they would soon enter labor. Supplemental Table 7 shows a full accounting of the experiments in panels B and C.