Hanna Huebner1, Andrea Hartner2, Wolfgang Rascher2, Reiner R Strick1, Sven Kehl1, Felix Heindl1, David L Wachter3, Matthias W Beckmann Md1, Fabian B Fahlbusch2, Matthias Ruebner1. 1. 1 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany. 2. 2 Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany. 3. 3 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany * The authors are contributed equally.
Abstract
INTRODUCTION: Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. METHODS: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg-3 cells with different RA derivates and 2'-deoxy-5-azacytidine (AZA) to induce DNA demethylation. RESULTS: RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines. DISCUSSION: RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication.
INTRODUCTION:Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. METHODS: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg-3 cells with different RA derivates and 2'-deoxy-5-azacytidine (AZA) to induce DNA demethylation. RESULTS:RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines. DISCUSSION: RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication.
Authors: Maria A Nieves-Colón; Keyla M Badillo Rivera; Karla Sandoval; Vanessa Villanueva Dávalos; Luis E Enriquez Lencinas; Javier Mendoza-Revilla; Kaustubh Adhikari; Ram González-Buenfil; Jessica W Chen; Elisa T Zhang; Alexandra Sockell; Patricia Ortiz-Tello; Gloria Malena Hurtado; Ramiro Condori Salas; Ricardo Cebrecos; José C Manzaneda Choque; Franz P Manzaneda Choque; Germán P Yábar Pilco; Erin Rawls; Celeste Eng; Scott Huntsman; Esteban Burchard; Andrés Ruiz-Linares; Rolando González-José; Gabriel Bedoya; Francisco Rothhammer; Maria Cátira Bortolini; Giovanni Poletti; Carla Gallo; Carlos D Bustamante; Julie C Baker; Christopher R Gignoux; Genevieve L Wojcik; Andrés Moreno-Estrada Journal: Am J Hum Genet Date: 2022-05-18 Impact factor: 11.043
Authors: Alexander Mocker; Marius Schmidt; Hanna Huebner; Rainer Wachtveitl; Nada Cordasic; Carlos Menendez-Castro; Andrea Hartner; Fabian B Fahlbusch Journal: Int J Mol Sci Date: 2019-12-29 Impact factor: 5.923