Dataset Information

MiRNAs as common regulators of the transforming growth factor (TGF)-? pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

ABSTRACT: Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus/placenta. While the etiology is unknown, poor placentation due to aberrant signaling of growth and angiogenic factors has been postulated as a causal factor of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity and increased risk of developing PE. Here, we use a translational study design to investigate genomic and epigenomic alterations in both placentas and placental trophoblasts, focused on the angiogenesis-associated transforming growth factor-beta (TGF-?) pathway. Genes within the TGF-? pathway displayed increased expression in both the preeclamptic placenta and Cd-treated trophoblasts. In addition, miRNAs that target the TGF-? pathway were also significantly altered within the preeclamptic placenta and Cd-treated trophoblasts. Integrative analysis resulted in the identification of a subset of Cd-responsive miRNAs, including miR-26a and miR-155, common to preeclamptic placentas and Cd-treated trophoblasts. These miRNAs have previously been linked to PE and are predicted to regulate members of the TGF-? pathway. Results from this study provide future targets for PE treatment.

SUBMITTER: Brooks SA

PROVIDER: S-EPMC5156314 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

Brooks Samira A SA Martin Elizabeth E Smeester Lisa L Grace Matthew R MR Boggess Kim K Fry Rebecca C RC

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 20160629 Pt A

Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus/placenta. While the etiology is unknown, poor placentation due to aberrant signaling of growth and angiogenic factors has been postulated as a causal factor of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity ...[more]

PMID: 27375191

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Project description:Significance During pregnancy, extravillous trophoblasts (EVTs) detach from anchoring sites of the placenta, differentiate, and invade the maternal uterus to remodel its vasculature. Failures in this program contribute to placentation defects observed in gestational disorders such as spontaneous pregnancy loss, early-onset preeclampsia, and fetal growth restriction. However, critical regulators and signaling pathways controlling EVT development have been poorly elucidated. In the present study, we demonstrate that transforming growth factor-β (TGF-β) signaling plays a pivotal role in the differentiation program of EVTs. In vitro, loss of Wingless signaling was sufficient for EVT formation in self-renewing trophoblast models, whereas subsequent activation of TGF-β signaling accomplished differentiation into trophoblasts that display some features of in vivo EVTs. Abnormal placentation has been noticed in a variety of pregnancy complications such as miscarriage, early-onset preeclampsia, and fetal growth restriction. Defects in the developmental program of extravillous trophoblasts (EVTs), migrating from placental anchoring villi into the maternal decidua and its vessels, is thought to be an underlying cause. Yet, key regulatory mechanisms controlling commitment and differentiation of the invasive trophoblast lineage remain largely elusive. Herein, comparative gene expression analyses of HLA-G–purified EVTs, isolated from donor-matched placenta, decidua, and trophoblast organoids (TB-ORGs), revealed biological processes and signaling pathways governing EVT development. In particular, bioinformatics analyses and manipulations in different versatile trophoblast cell models unraveled transforming growth factor-β (TGF-β) signaling as a crucial pathway driving differentiation of placental EVTs into decidual EVTs, the latter showing enrichment of a secretory gene signature. Removal of Wingless signaling and subsequent activation of the TGF-β pathway were required for the formation of human leukocyte antigen-G+ (HLA-G+) EVTs in TB-ORGs that resemble in situ EVTs at the level of global gene expression. Accordingly, TGF-β–treated EVTs secreted enzymes, such as DAO and PAPPA2, which were predominantly expressed by decidual EVTs. Their genes were controlled by EVT-specific induction and genomic binding of the TGF-β downstream effector SMAD3. In summary, TGF-β signaling plays a key role in human placental development governing the differentiation program of EVTs.

Dataset Information

MiRNAs as common regulators of the transforming growth factor (TGF)-? pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

Publications

miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

Similar Datasets

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