title: Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia.
abstract: Preeclampsia is a unique multiple system disorder during human pregnancy, which affects ≈5% to 8% of pregnancies. Its risks and complications have become the major causes of maternal and fetal morbidity and mortality. Although abnormal placentation to which DNA methylation dysregulation is always linked is speculated to be one of the reasons causing preeclampsia, the underlying mechanisms still remain elusive to date. Here we revealed that aberrant DNA methyltransferase 3A (DNMT3A) plays a critical role in preeclampsia. Our results show that the expression and localization of DNMT3A are dysregulated in preeclamptic placenta. Moreover, knockdown of DNMT3A obviously inhibits trophoblast cell migration and invasion. Mechanistically, IGFBP5 (insulin-like growth factor-binding protein 5), known as a suppressor, is upregulated by decreased DNMT3A because of promoter hypomethylation. Importantly, IGFBP5 downregulation can rescue the defects caused by DNMT3A knockdown, thereby, consolidating the significance of IGFBP5 in the downstream of DNMT3A in trophoblast. Furthermore, we detected low promoter methylation and high protein expression of IGFBP5 in the clinical samples of preeclamptic placenta. Collectively, our study suggests that dysregulation of DNMT3A and IGFBP5 is relevant to preeclampsia. Thus, we propose that DNMT3A and IGFBP5 can serve as potential markers and targets for the clinical diagnosis and therapy of preeclampsia.
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Yuanhui
authors.initials: Y
authors.lastname: Jia
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Huang
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Xianghong
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Xinyao
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Linyan
authors.initials: L
authors.lastname: Jia
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Jingping
authors.initials: J
authors.lastname: Zhu
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Dandan
authors.initials: D
authors.lastname: Xie
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang).
authors.forename: Liping
authors.initials: L
authors.lastname: Jin
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang). jqzhang@bio.ecnu.edu.cn tduan@yahoo.com.
authors.forename: Jiqin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Clinical and Translational Research Center (Y.J., X.H., X.X., X.Z., L. Jia, J. Zhu, D.X., K.W., Q.Z., L. Jin) and Department of Obstetrics (T.L., T.D.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China; and Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (J. Zhang). jqzhang@bio.ecnu.edu.cn tduan@yahoo.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Duan
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005260:Female; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000096:biosynthesis / Q000235:genetics*; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: C000717967:DNMT3A protein, human; D018975:Insulin-Like Growth Factor Binding Protein 5; D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA methylation; DNMT3A; IGFBP5; migration and invasion; preeclampsia; trophoblast