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      Preeclampsia-Associated lncRNA INHBA-AS1 Regulates the Proliferation, Invasion, and Migration of Placental Trophoblast Cells

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          Abstract

          Preeclampsia is believed to be caused by impaired placentation with insufficient trophoblast invasion, leading to impaired uterine spiral artery remodeling and angiogenesis. However, the underlying molecular mechanism remains unknown. We recently carried out transcriptome profiling of placental long noncoding RNAs (lncRNAs) and identified 383 differentially expressed lncRNAs in early-onset severe preeclampsia. Here, we are reporting our identification of lncRNA INHBA-AS1 as a potential causal factor of preeclampsia and its downstream pathways that may be involved in placentation. We found that INHBA-AS1 was upregulated in patients and positively correlated with clinical severity. We systematically searched for potential INHBA-AS1-binding transcription factors and their targets in databases and found that the targets were enriched with differentially expressed genes in the placentae of patients. We further demonstrated that the lncRNA INHBA-AS1 inhibited the invasion and migration of trophoblast cells through restraining the transcription factor CENPB from binding to the promoter of TNF receptor-associated factor 1 ( TRAF1). Therefore, we have identified the dysregulated pathway “ INHBA-AS1-CENPB-TRAF1” as a contributor to the pathogenesis of preeclampsia through prohibiting the proliferation, invasion, and migration of trophoblasts during placentation.

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          Abstract

          Preeclampsia is believed to be caused by impaired placentation. Xinping Yang and colleagues report the identification of lncRNA INHBA-AS1 as a potential causal factor of preeclampsia. They found that INHBA-AS1 is positively correlated with clinical severity and involved in the pathogenesis through inhibiting the invasion and migration of trophoblast cells.

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          Most cited references 69

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          Pre-eclampsia part 1: current understanding of its pathophysiology.

          Pre-eclampsia is characterized by new-onset hypertension and proteinuria at ≥20 weeks of gestation. In the absence of proteinuria, hypertension together with evidence of systemic disease (such as thrombocytopenia or elevated levels of liver transaminases) is required for diagnosis. This multisystemic disorder targets several organs, including the kidneys, liver and brain, and is a leading cause of maternal and perinatal morbidity and mortality. Glomeruloendotheliosis is considered to be a characteristic lesion of pre-eclampsia, but can also occur in healthy pregnant women. The placenta has an essential role in development of this disorder. Pathogenetic mechanisms implicated in pre-eclampsia include defective deep placentation, oxidative and endoplasmic reticulum stress, autoantibodies to type-1 angiotensin II receptor, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and the presence of an antiangiogenic state, among which an imbalance of angiogenesis has emerged as one of the most important factors. However, this imbalance is not specific to pre-eclampsia, as it also occurs in intrauterine growth restriction, fetal death, spontaneous preterm labour and maternal floor infarction (massive perivillous fibrin deposition). The severity and timing of the angiogenic imbalance, together with maternal susceptibility, might determine the clinical presentation of pre-eclampsia. This Review discusses the diagnosis, classification, clinical manifestations and putative pathogenetic mechanisms of pre-eclampsia.
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            A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.

            To investigate trophoblast invasion and vascular changes in placental bed spiral arteries in normal and severe pre-eclamptic pregnancies. A histological and immunohistochemical study of placental bed biopsies containing spiral arteries. The University Hospital, Leuven, Belgium. Twenty-one placental bed biopsies from 21 normal pregnancies and 24 placental bed biopsies from 24 severe pre-eclamptic pregnancies, taken at caesarean section. Histological and immunohistochemical appearance of spiral arteries (stained with haematoxylin and eosin), periodic acid schiff, and a monoclonal antibody to low molecular weight cytokeratin. One hundred and twenty-seven spiral arteries were studied. In the 21 biopsies from clinically normal pregnancies at term, 100% of the decidual spiral arteries and 76% of the myometrial arteries showed trophoblast invasion. In the 24 biopsies from women with severe pre-eclampsia, trophoblast invasion was seen in 44% and 18% of the decidual and myometrial segments, respectively. Endovascular trophoblast invasion was complete, partial or isolated. A variety of morphological features was present not only in different spiral arteries from the same biopsy but also in different segments of the same artery. The vascular change most commonly associated with normal pregnancies was physiological change and subintimal thickening of both segments of the spiral arteries. In pre-eclampsia medial disorganisation and hyperplasia in the myometrial arteries and acute atherosis in decidual arteries were common. Endovascular trophoblast did not show an all or none invasive phenomenon in normal and pre-eclamptic pregnancies. More decidual than myometrial arteries were invaded in both groups of patients, and there was a gradient in the percentage of decidual and myometrial arteries invaded from normal pregnancy to pre-eclampsia. Morphological features in one spiral artery may not necessarily be representative of all of those in a placental bed.
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              ITFP: an integrated platform of mammalian transcription factors.

              Investigation of transcription factors (TFs) and their downstream regulated genes (targets) is a significant issue in post-genome era, which can provide a brand new vision for some vital biological process. However, information of TFs and their targets in mammalian is far from sufficient. Here, we developed an integrated TF platform (ITFP), which included abundant TFs and their targets of mammalian. In current release, ITFP includes 4105 putative TFs and 69 496 potential TF-target pairs for human, 3134 putative TFs and 37 040 potential TF-target pairs for mouse, and 1114 putative TFs and 18 055 potential TF-target pairs for rat. In short, ITFP will serve as an important resource for the research community of transcription and provide strong support for regulatory network study.
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                Author and article information

                Contributors
                Journal
                Mol Ther Nucleic Acids
                Mol Ther Nucleic Acids
                Molecular Therapy. Nucleic Acids
                American Society of Gene & Cell Therapy
                2162-2531
                09 October 2020
                04 December 2020
                09 October 2020
                : 22
                : 684-695
                Affiliations
                [1 ]Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
                [2 ]Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou 510515, China
                [3 ]Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
                Author notes
                []Corresponding author: Xinping Yang, Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. xpyang1@ 123456smu.edu.cn
                [4]

                These authors contributed equally to this work.

                Article
                S2162-2531(20)30304-8
                10.1016/j.omtn.2020.09.033
                7585871
                © 2020 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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