p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction
| Autor: | Ihsan Gadi, Hanna Huebner, Moh'd Mohanad Al-Dabet, Anat Aharon, Juliane Hoffmann, Shrey Kohli, Jayakumar Manoharan, Michael Löttge, Berend Isermann, Paulina Markmeyer, Franziska Lochmann, Khurrum Shahzad, Matthias Ruebner, Fabian B. Fahlbusch, Benjamin Brenner, Ana Claudia Zenclussen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death medicine.medical_specialty Cellular differentiation Immunology SUMO protein 8-Bromo Cyclic Adenosine Monophosphate Apoptosis Placental insufficiency Biology 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Syncytiotrophoblast Pregnancy Internal medicine medicine Animals Humans Transcription factor reproductive and urinary physiology Gene knockdown 030219 obstetrics & reproductive medicine Fetal Growth Retardation Caspase 3 Trophoblast Nuclear Proteins Sumoylation Acetylation Cell Differentiation Cell Biology medicine.disease female genital diseases and pregnancy complications Cell biology Trophoblasts DNA-Binding Proteins 030104 developmental biology Endocrinology medicine.anatomical_structure NF-E2 Transcription Factor p45 Subunit embryonic structures Female Original Article Protein Processing Post-Translational Transcription Factors |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Placental insufficiency jeopardizes prenatal development, potentially leading to intrauterine growth restriction (IUGR) and stillbirth. Surviving fetuses are at an increased risk for chronic diseases later in life. IUGR is closely linked with altered trophoblast and placental differentiation. However, due to a paucity of mechanistic insights, suitable biomarkers and specific therapies for IUGR are lacking. The transcription factor p45 NF-E2 (nuclear factor erythroid derived 2) has been recently found to regulate trophoblast differentiation in mice. The absence of p45 NF-E2 in trophoblast cells causes IUGR and placental insufficiency in mice, but mechanistic insights are incomplete and the relevance of p45 NF-E2 for human syncytiotrophoblast differentiation remains unknown. Here we show that p45 NF-E2 negatively regulates human syncytiotrophoblast differentiation and is associated with IUGR in humans. Expression of p45 NF-E2 is reduced in human placentae complicated with IUGR compared with healthy controls. Reduced p45 NF-E2 expression is associated with increased syncytiotrophoblast differentiation, enhanced glial cells missing-1 (GCM1) acetylation and GCM1 desumoylation in IUGR placentae. Induction of syncytiotrophoblast differentiation in BeWo and primary villous trophoblast cells with 8-bromo-adenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) reduces p45 NF-E2 expression. Of note, p45 NF-E2 knockdown is sufficient to increase syncytiotrophoblast differentiation and GCM1 expression. Loss of p45 NF-E2 using either approach resulted in CBP-mediated GCM1 acetylation and SENP-mediated GCM1 desumoylation, demonstrating that p45 NF-E2 regulates post-translational modifications of GCM1. Functionally, reduced p45 NF-E2 expression is associated with increased cell death and caspase-3 activation in vitro and in placental tissues samples. Overexpression of p45 NF-E2 is sufficient to repress GCM1 expression, acetylation and desumoylation, even in 8-Br-cAMP exposed BeWo cells. These results suggest that p45 NF-E2 negatively regulates differentiation and apoptosis activation of human syncytiotrophoblast by modulating GCM1 acetylation and sumoylation. These studies identify a new pathomechanism related to IUGR in humans and thus provide new impetus for future studies aiming to identify new biomarkers and/or therapies of IUGR. |
| Databáze: | OpenAIRE |
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