Chelbi Sonia T, Mondon Françoise, Jammes Hélène, Buffat Christophe, Mignot Thérèse-Marie, Tost Jorg, Busato Florence, Gut Ivo, Rebourcet Régis, Laissue Paul, Tsatsaris Vassili, Goffinet François, Rigourd Virginie, Carbonne Bruno, Ferré Françoise, Vaiman Daniel
Equipe 21, 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.
Hypertension. 2007 Jan;49(1):76-83. doi: 10.1161/01.HYP.0000250831.52876.cb. Epub 2006 Nov 6.
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 >or=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.
子痫前期是主要的妊娠高血压疾病。它会改变胎盘基因的表达谱，包括几种丝氨酸蛋白酶抑制剂（SERPINs）。本研究的目的是对这些基因在正常和病理胎盘组织中进行系统的表达分析，并确定其启动子区域内的表观遗传改变。通过定量逆转录聚合酶链反应（RT-PCR）对患有子痫前期、胎儿生长受限或两者兼有的妊娠胎盘组织中18种胎盘SERPINs的表达进行分析，并与正常对照进行比较。SERPINA3、A5、A8、B2、B5和B7在≥1种病理情况下的表达存在显著差异。同时，在对照和子痫前期胎盘组织样本中研究了位于其启动子区域的CpG岛的甲基化状态。10种SERPIN启动子要么完全甲基化，要么完全未甲基化，而SERPINA3、A5和A8呈现出复杂的甲基化谱。对于SERPINA3，分析扩展至81个样本并采用焦磷酸测序法进行。对于SERPINA3 CpG岛，子痫前期和生长受限情况下的平均甲基化水平显著降低。低甲基化的CpG位于发育和应激反应（缺氧和炎症）因子的假定结合位点。我们的研究结果首次观察到人类胎盘疾病中一种特定的表观遗传改变，并为早期诊断提供了新的潜在标志物。
