title: DREAM mediated regulation of GCM1 in the human placental trophoblast.
abstract: The trophoblast transcription factor glial cell missing-1 (GCM1) regulates differentiation of placental cytotrophoblasts into the syncytiotrophoblast layer in contact with maternal blood. Reduced placental expression of GCM1 and abnormal syncytiotrophoblast structure are features of hypertensive disorder of pregnancy--preeclampsia. In-silico techniques identified the calcium-regulated transcriptional repressor--DREAM (Downstream Regulatory Element Antagonist Modulator)--as a candidate for GCM1 gene expression. Our objective was to determine if DREAM represses GCM1 regulated syncytiotrophoblast formation. EMSA and ChIP assays revealed a direct interaction between DREAM and the GCM1 promoter. siRNA-mediated DREAM silencing in cell culture and placental explant models significantly up-regulated GCM1 expression and reduced cytotrophoblast proliferation. DREAM calcium dependency was verified using ionomycin. Furthermore, the increased DREAM protein expression in preeclamptic placental villi was predominantly nuclear, coinciding with an overall increase in sumolylated DREAM and correlating inversely with GCM1 levels. In conclusion, our data reveal a calcium-regulated pathway whereby GCM1-directed villous trophoblast differentiation is repressed by DREAM. This pathway may be relevant to disease prevention via calcium-supplementation.
authors.affiliation: Research Centre for Women's and Infants' Health at the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. baczyk@lunenfeld.ca
authors.forename: Dora
authors.initials: D
authors.lastname: Baczyk
authors.forename: Mark
authors.initials: M
authors.lastname: Kibschull
authors.forename: Britt
authors.initials: B
authors.lastname: Mellstrom
authors.forename: Khrystyna
authors.initials: K
authors.lastname: Levytska
authors.forename: Marcos
authors.initials: M
authors.lastname: Rivas
authors.forename: Sascha
authors.initials: S
authors.lastname: Drewlo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lye
authors.forename: Jose R
authors.initials: JR
authors.lastname: Naranjo
authors.forename: John C P
authors.initials: JC
authors.lastname: Kingdom
mesh_terms: D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology
chemical_list: C496756:Csen protein, mouse; D004268:DNA-Binding Proteins; C491089:GCM1 protein, human; C101631:Gcm1 protein, mouse; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D002118:Calcium