FocusReproductive Biology

Glucocorticoid signaling drives epigenetic and transcription factors to induce key regulators of human parturition

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Science Signaling  27 Oct 2015:
Vol. 8, Issue 400, pp. fs19
DOI: 10.1126/scisignal.aad3022

Abstract

Glucocorticoids are thought to play an important role in parturition. Two recent articles by Di Stefano et al. in the Archives and Wang et al. in this issue of Science Signaling reveal novel mechanisms by which glucocorticoid signaling can drive the epigenetic and transcriptional machinery to induce molecules involved in parturition, including the neuropeptide corticotropin-releasing hormone (CRH), the enzyme cyclooxygenase-2 (COX-2), and the autacoid hormone prostaglandin E2. These findings contribute to our understanding of how glucocorticoids may regulate human parturition.

Stress responses comprise a repertoire of molecular, hormonal, neural, and behavioral adaptations to challenges that threaten organism survival and homeostasis. At the molecular level, these responses are to a large extent mediated by the actions of glucocorticoids, the end product of the hypothalamic-pituitary-adrenal (HPA) axis. This conserved axis is set into motion by the hypothalamus, a brain region that integrates stressful stimuli and signals the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH then promotes adrenal secretion of glucocorticoids (1), which circulate and exert actions in essentially every body tissue primarily via activation of two receptors, the mineralocorticoid receptor and the glucocorticoid receptor (GR). Stress responses and glucocorticoid secretion can be triggered by a number of environmental and physiological changes, and their aim is to promote organism adaptation and homeostasis.

Parturition, the culmination of normal pregnancy, encompasses a set of highly stressful physiological changes. Successful adaptation to these changes is essential, because the proper initiation and progress of parturition is a crucial determinant of pregnancy duration, fetal development, and delivery of a healthy child. Improperly timed parturition can result in preterm or postterm births, which continue to occur in up to 20% of all pregnancies and account for the majority of perinatal complications, morbidity, and mortality (2, 3). Notably, a large percentage of mistimed labors are unexplained (4), a reflection of our limited insights into the molecular mechanisms that govern the initiation and progress of labor.

Among molecules that regulate parturition, a prominent role has been ascribed to glucocorticoids, ubiquitous pleiotropic hormones that can prepare tissues for and trigger labor in several animal species. They rise gradually over the course of human gestation and can stimulate gestational tissue production of molecules that have important roles in parturition. These molecules include corticotropin-releasing hormone (CRH); cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis; and prostaglandins (3, 5, 6). Interestingly, the intracellular signaling cascades through which glucocorticoids influence these molecules are largely unknown.

Addressing this knowledge gap, two recently published articles in Science Signaling show novel roles of glucocorticoids in human parturition. The article by Di Stefano et al. (7) builds on the previously identified cross-talk between glucocorticoid signaling and the noncanonical nuclear factor κB (NF-κB) pathway (RelB/p52), a known intermediate of glucocorticoid-mediated induction of CRH. Examining human placental cytotrophoblasts, the authors found that the synthetic GR agonist dexamethasone induces CRH but also COX-2 via an “epigenetic switch” that operates in a time-dependent manner. This switch is “turned on” in the full-term but not the mid-trimester placenta by dynamic histone 3 Lys9 acetylation and deacetylation (H3K9ac) of the CRH and COX-2 gene promoters. The glucocorticoid-driven H3K9ac turnover depends on the GR and RelB/p52 transcription factors, which recruit the histone acetyltransferase CREB-binding protein (CBP) and histone deacetylase-1 (HDAC1) to the target promoter sites. Together, these findings show that GR/RelB/p52 signaling epigenetically up-regulates the expression of the CRH and COX-2 genes in placental cytotrophoblasts.

The other article, by Wang et al., further builds on the molecular mechanisms that drive induction of COX-2 by glucocorticoids (8). Examining human amnion fibroblasts, the authors found that cortisol promotes interaction of the GR with two transcription factors, signal transducer and activator of transcription 3 (STAT3) and cyclic adenosine monophosphate response element binding protein–1 (CREB). These interactions facilitate phosphorylation of both transcription factors by the kinases PKA and SRC. The transcriptional complex then translocates into the nucleus and binds to the COX-2 promoter region to induce expression of COX-2, eventually leading to increased production of prostaglandin E2 (PGE2). PGE2 in turn activates its receptors EP2 and EP4 in an autocrine fashion to induce phosphorylation of STAT3, further promoting the translocation of the GR/STAT3/CREB complex to the nucleus. These findings suggest that PGE2 and cortisol synergize to form a feedforward mechanism that up-regulates COX-2 expression and PGE2 synthesis and production in amnion fibroblasts.

The results of the two articles are schematically summarized in Fig. 1. Although these reports contribute to our understanding of how glucocorticoid signaling influences human parturition, an important question remains as to how glucocorticoid-mediated effects across different tissues and pathways could be integrated over the course of gestation and parturition. One contributing mechanism appears to be the presence of multiple cortisol-driven feedback and feedforward loops that operate in a tissue-specific manner. Thus, as circulating cortisol concentrations rise with the progression of pregnancy, levels of the glucocorticoid further increase locally in gestational tissues (3, 5). This is achieved in fetal membranes via a positive feedback mechanism that involves cortisol-mediated induction of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), the enzyme that converts inactive cortisone to cortisol (9).

Fig. 1 Glucocorticoid pathways in labor.

Glucocorticoid signaling in gestational tissues drives epigenetic and transcription factors to induce key regulators of human parturition. These mechanisms may eventually contribute to the initiation and progression of parturition. Aberrant glucocorticoid signaling—for example, in the context of chronic or excessive stress—may increase the risk for mistimed (preterm or postterm) labor.

CREDIT: P. HUEY/SCIENCE SIGNALING

As shown by Wang et al., an additional feedforward mechanism operates in amnion fibroblasts, leading to a synergistic effect of cortisol and PGE2 on GR/CREB/STAT3 signaling that induces transcription of the gene encoding COX-2 and production of PGE2. Therefore, glucocorticoid signaling may show enhanced activity and specific effects in gestational tissues regulating human parturition. Another point of integration may be at the level of the chromatin landscape of glucocorticoid-responsive genes related to gestation and parturition. For example, the responsivity of COX-2 to transcription factors is likely to be modulated by the chromatin conformation of the gene locus and its interaction with regulatory elements, which in turn can be shaped by the epigenetic state of these genomic sites. As shown by Di Stefano et al., a glucocorticoid-induced epigenetic modification that can modulate COX-2 expression is H3K9ac turnover at the gene promoter site.

Beyond such dynamic modifications, cortisol may also induce lasting epigenetic changes, a form of molecular memory that shapes subsequent transcriptional responsivity. For instance, glucocorticoid binding to glucocorticoid response elements can induce DNA demethylation that leads to derepressed transcriptional responses to subsequent glucocorticoid exposure (10). Epigenetic changes could thus reflect to some extent the molecular history of gestational tissue exposure to cortisol during pregnancy. We expect that cortisol-driven epigenetic modifications will be increasingly recognized as important contributors to a “gestational clock” that eventually triggers initiation and progress of parturition. The exact mechanisms that temporally integrate the effects of glucocorticoid on distinct components of the epigenetic and transcriptional machinery to ultimately regulate human parturition remain to be tested in future studies.

Uncovering the molecular role of glucocorticoids in parturition could have important implications for the prevention and treatment of mistimed labors. Conditions associated with aberrant glucocorticoid signaling, such as work-related or interpersonal stressors, are ubiquitous in modern societies and represent a major risk factor for mistimed labors (4). Nonetheless, the specific stressor characteristics that account for these detrimental effects (such as stressor timing, type, and duration) and their underlying molecular mechanisms remain poorly understood. Molecular insights into the cross-talk of distinct pathways regulating parturition could also contribute to novel treatments for preterm and postterm labors. For instance, anti-inflammatory prostaglandins that inhibit the NF-κΒ pathway have been proposed as promising treatments for preterm labor (11). Similarly, the development of molecules that target the interaction of glucocorticoid signaling with specific pathways, as well as individualization of treatment (such as by selective treatment of individuals exposed to high levels of stressors or other risk factors), could improve pregnancy outcomes and minimize adverse treatment effects.

REFERENCES AND NOTES

Funding: A.S.Z. is supported by a Marie-Sklodowska Curie fellowship (H2020 grant no. 653240). Competing interests: The authors declare no financial conflicts of interest.
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