Published Online
on November 6, 2006

A more recent version of this article appeared on January 1, 2007

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Submitted on August 21, 2006
Revised on September 11, 2006

Expressional and Epigenetic Alterations of Placental Serine Protease Inhibitors. SERPINA3 Is a Potential Marker of Preeclampsia

Sonia T. Chelbi; Françoise Mondon; Hélène Jammes; Christophe Buffat; Thérèse-Marie Mignot; Jorg Tost; Florence Busato; Ivo Gut; Régis Rebourcet; Paul Laissue; Vassili Tsatsaris; François Goffinet; Virginie Rigourd; Bruno Carbonne; Françoise Ferré; and Daniel Vaiman^*

From the Equipe 21 (S.T.C., F.M., H.J., T.-M.M., R.R., P.L., B.C., V.R., B.C., F.F., D.V.), Génomique et Epigénétique des Pathologies Placentaires, Unité INSERM 567/UMR Centre National de la Recherche Scientifique 8104, Université Paris V IFR Alfred Jost, Faculté de Médecine, Cochin-Port-Royal, Paris, France; PHASE Department (H.J.), Institut National de la Recherche Agronomique, Jouy-en-Josas, France; Faculté de Médecine (C.B.), Université de la Méditerranée et Service de Néonatologie, Hôpital de la Conception AP-HM, Marseille, France; Laboratoire d’épigénétique (J.T., F.B., I.G.), Centre National de Génotypage, Evry, France; Service de Gynécologie-Obstétrique (V.T., F.G.), Université Paris V, Faculté de Médecine, APHP, Hôpital Cochin, Paris, France; Service de Gynécologie-Obstétrique (B.C.), Hôpital Saint Antoine, Paris, France; and the Animal Genetics Department (D.V.), Institut National de la Recherche Agronomique Jouy-en-Josas, France.

^* To whom correspondence should be addressed. E-mail: vaiman{at}cochin.inserm.fr.

Abstract--Preeclampsia is the major pregnancy-induced hypertensive disorder. It modifies the expression profile of placental genes, including several serine protease inhibitors (SERPINs). The objective of this study was to perform a systematic expression analysis of these genes in normal and pathological placentas and to pinpoint epigenetic alterations inside their promoter regions. Expression of 18 placental SERPINs was analyzed by quantitative RT-PCR on placentas from pregnancies complicated by preeclampsia, intrauterine growth restriction, or both and was compared with normal controls. SERPINA3, A5, A8, B2, B5, and B7 presented significant differences in expression in 1 pathological situation. In parallel, the methylation status of the CpG islands located in their promoter regions was studied on a sample of control and preeclamptic placentas. Ten SERPIN promoters were either totally methylated or totally unmethylated, whereas SERPINA3, A5, and A8 presented complex methylation profiles. For SERPINA3, the analysis was extended to 81 samples and performed by pyrosequencing. For the SERPINA3 CpG island, the average methylation level was significantly diminished in preeclampsia and growth restriction. The hypomethylated CpGs were situated at putative binding sites for developmental and stress response (hypoxia and inflammation) factors. Our results provide one of the first observations of a specific epigenetic alteration in human placental diseases and provide new potential markers for an early diagnosis.

Key words: preeclampsia • intrauterine growth restriction • placenta • serine protease inhibitors • epigenetics

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