title: Genetic and epigenetic mechanisms collaborate to control SERPINA3 expression and its association with placental diseases.
abstract: SERPINA3 (Serpin peptidase inhibitor clade A member 3), also known as a1-antichymotrypsin, is a serine protease inhibitor involved in a wide range of biological processes. Recently, it has been shown to be up-regulated in human placental diseases in association with a hypomethylation of the 5' region of the gene. In the present study, we show that the promoter of SERPINA3 is transcriptionally activated by three transcription factors (TFs) (SP1, MZF1 and ZBTB7B), the level of induction being dependent on the rs1884082 single nucleotide polymorphism (SNP) located inside the promoter, the T allele being consistently induced to a higher level than the G, with or without added TFs. When the promoter was methylated, the response to ZBTB7B was allele specific (the G allele was strongly induced, while the T allele was strongly down-regulated). We propose an adaptive model to explain the interest of such a regulation for placental function and homeostasis. Overexpression of SERPINA3 in JEG-3 cells, a trophoblast cell model, decreased cell adhesion to the extracellular matrix and to neighboring cells, but protects them from apoptosis, suggesting a way by which this factor could be deleterious at high doses. In addition, we show in different human populations that the T allele appears to predispose to Intra Uterine Growth Restriction (IUGR), while a G allele at a second SNP located in the second exon (rs4634) increases the risk of preeclampsia. Our results provide mechanistic views inside the involvement of SERPINA3 in placental diseases, through its regulation by a combination of epigenetic, genetic and TF-mediated regulations.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris, France.
authors.forename: Sonia T
authors.initials: ST
authors.lastname: Chelbi
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Wilson
authors.forename: Anne-Clémence
authors.initials: AC
authors.lastname: Veillard
authors.forename: Sue A
authors.initials: SA
authors.lastname: Ingles
authors.forename: Jim
authors.initials: J
authors.lastname: Zhang
authors.forename: Françoise
authors.initials: F
authors.lastname: Mondon
authors.forename: Géraldine
authors.initials: G
authors.lastname: Gascoin-Lachambre
authors.forename: Ludivine
authors.initials: L
authors.lastname: Doridot
authors.forename: Thérèse-Marie
authors.initials: TM
authors.lastname: Mignot
authors.forename: Régis
authors.initials: R
authors.lastname: Rebourcet
authors.forename: Bruno
authors.initials: B
authors.lastname: Carbonne
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Concordet
authors.forename: Sandrine
authors.initials: S
authors.lastname: Barbaux
authors.forename: Daniel
authors.initials: D
authors.lastname: Vaiman
mesh_terms: D000483:Alleles; D017209:Apoptosis; D001483:Base Sequence; D016022:Case-Control Studies; D002448:Cell Adhesion; D002460:Cell Line; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008954:Models, Biological; D010922:Placenta Diseases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D012333:RNA, Messenger; C516148:SERPINA3 protein, human; D015843:Serpins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C484225:ZBTB7B protein, human