title: The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1).
abstract: Preeclampsia is a pregnancy-specific syndrome mainly characterized by hypertensive disorder and proteinuria after gestational weeks 20. So far the etiology of preeclampsia remains unclear. We previously reported that preeclamptic placentas exhibited decreased mRNA expression and hypermethylation in promoter region of the paternally imprinted H19 gene compared with normal placentas. H19 has recently been identified to encode the precursor of miR-675, indicating a possible novel functional pathway of the imprinting gene. The aim of the present study was to identify the roles of H19 gene via miR-675 pathway in human trophoblast cells, and to figure out the involvement of this pathway in pathogenesis of preeclampsia. Knockdown of H19 gene or inhibition of miR-675 exhibited similar proliferation-promoting effect in human trophoblastic JEG-3 cells. Target gene prediction in combination with luciferase assay revealed that miR-675 could directly downregulate Nodal Modulator 1 (NOMO1) protein expression by binding to 3'-UTR sequence of NOMO1. Overexpression of NOMO1 in JEG-3 cells could rescue miR-675-surppressed cell proliferation and phosphorylation of Smad2, while Nodal had additive effect with miR-675 in suppression cell proliferation and activation of Smad2. In early-onset preeclamptic placentas, expression levels of H19 gene and miR-675 were appreciably lower, while NOMO1 protein level was higher than those in normal placentas. Taken together, our data suggested that H19 gene could inhibit human trophoblast cell proliferation via encoding miR-675 that targeted NOMO1, and aberrantly lowered expression of H19 in placenta may participate in the excessive proliferation of trophoblast cells observed in early-onset severe preeclampsia by downregulating miR-675 which targets NOMO1 and interferes with Nodal signaling.
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors: Wen-Long
authors: WL
authors: Gao
authors: Ming
authors: M
authors: Liu
authors: Yanyan
authors: Y
authors: Yang
authors: Huixia
authors: H
authors: Yang
authors: Qinping
authors: Q
authors: Liao
authors: Yang
authors: Y
authors: Bai
authors: Yu-Xia
authors: YX
authors: Li
authors: Dong
authors: D
authors: Li
authors: Chun
authors: C
authors: Peng
authors: Yan-Ling
authors: YL
authors: Wang
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D055457:Nodal Protein / Q000502:physiology; D010920:Placenta / Q000473:pathology*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: C094335:H19 long non-coding RNA; D047908:Intracellular Signaling Peptides and Proteins; C548379:MIRN675 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C526007:NODAL protein, human; C501109:NOMO3 protein, human; D055457:Nodal Protein; D062085:RNA, Long Noncoding