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H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition
Patrice Nancy, … , Aristotelis Tsirigos, Adrian Erlebacher
Patrice Nancy, … , Aristotelis Tsirigos, Adrian Erlebacher
Published November 27, 2017
Citation Information: J Clin Invest. 2018;128(1):233-247. https://doi.org/10.1172/JCI95937.
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Research Article Reproductive biology

H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition

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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 3

H3K27me3 accrual in DSCs prevents fibroblast activation/myofibroblast formation and wound healing in the decidua.

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H3K27me3 accrual in DSCs prevents fibroblast activation/myofibroblast fo...
(A–C) RNA-Seq analysis of DSCs, MSCs, and USCs, and the relationship of gene expression to H3K27me3 marking. Distribution of mRNA expression differences (Padj < 0.05; n = 3 samples/group), binned into progressive 2-fold changes. *P < 5.6 × 10–3, significantly over- (orange) or underrepresented (gray) for DSC>MSC targets as compared with expectation. (D) DSC>MSC H3K27me3 targets within all genes with significantly different expression both between MSCs and USCs and between DSCs and USCs. (E) H3K27me3 marking and mRNA expression of DSC>MSC targets involved in fibroblast activation/myofibroblast formation. The 15 genes with rankings are from the upper left quadrant of D and encode the classical markers FAP (12), CXCL12 (12), THY1 (14), and PDGFRB (12), proteins with less extensive literature such as IGFBP-5 (45), C-type natriuretic peptide (46), P311 (13), CXCL16 (47), integrin α11 (13), PAR2 (48), TRPC3 (49), and IL-33 (50), and several Wnt-signaling regulators induced during fibrosis or themselves profibrotic (13, 51). Although their expression was not increased in MSCs compared with USCs, other DSC>MSC targets included Acta2 (α-SMA) (13) and Cspg6 (14), 2 other major myofibroblast markers, as well as Agtr1a (14), Irf5, Pdpn (12), Tcf21 (14), Trpc6 (14), and Zeb1 (12), encoding additional emerging markers or inducers (bottom set). (F–I) Impaired wound healing responses in the decidua. Paired horns of undecidualized uteri were left unmanipulated (F) or scratched along their inner surface with a needle (G). Note the autofluorescent RBCs at the wound site (arrow). Representative images from 5 mice. Artificial decidua were wounded via injection with EGFP-expressing lentiviruses. Note the extravascular RBCs but minimal α-SMA staining at an injection site (H); the nearby myometrium was α-SMA+ (I). Representative images from 52 injection sites from 4 mice. Mice were sacrificed 2 days after scratching/injection.

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