H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition
Patrice Nancy, … , Aristotelis Tsirigos, Adrian Erlebacher
Patrice Nancy, … , Aristotelis Tsirigos, Adrian Erlebacher
Published January 2, 2018
Citation Information: J Clin Invest. 2018;128(1):233-247. https://doi.org/10.1172/JCI95937.
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Categories: 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 1

H3K27me3 generation in the postimplantation uterus.

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H3K27me3 generation in the postimplantation uterus. (A and B) Schematics...
(A and B) Schematics of ChIP-Seq comparisons. We considered only peaks that overlapped or were less than 5 kb upstream of the TSS (4,504 total). Stromal cells (DSCs, MSCs) were cultured for 24 hours after purification from artificially decidualized uteri (an abundant source of cells) on the day corresponding to E7.5. Comparisons between these cells (A; n = 3 each) tallied peaks that were significantly enriched more than 2-fold between populations (FDR < 0.05). Comparisons between whole tissues and tissue layers (B; n = 3 decidua and interimplantation site samples, n = 2 myometrium samples, all from true pregnancies on E7.5) employed the same overall peak set but, in consideration of the nonstromal cell contributions to the extracts, tallied those peaks with significantly different concentrations regardless of the degree of difference. (C, E, and F) Venn diagrams indicating the overlap between various peak sets. (D) Absolute concentrations of DSC>MSC peaks in stromal cell and whole-tissue layer extracts (mean ± SEM). Significant differences are indicated (unpaired t test). The lower concentration of peaks unique to the DSC>MSC data set brought their average concentration in decidual extracts into proximity with their average concentration in the whole-tissue myometrial extracts (red bar), which was not reduced in parallel. This precluded their scoring as enriched between tissue layers. Similar considerations applied to MSC>DSC peaks, which nonetheless already showed 60% overlap with myo>dec peaks (E, Supplemental Figure 1C). (G–J) EZH2 immunostaining of peri-implantation uteri. On E3.5 and in E6.5 interimplantation sites, EZH2 was expressed at low or undetectable levels by ESCs (G and H), whereas on E5.5 (not shown) and E6.5 (I), it was strongly expressed in most DSCs. Panels G–I are shown at the same magnification. Panel J is a close-up of panel I; note the nuclear accumulation of EZH2 in a large fraction of DSCs. CK8 identifies uterine epithelial cells and trophoblasts. DAPI counterstain. myo, myometrium; endo, endometrium; dec, decidua; e, embryo.