title: Hypermethylation of the HLA-G promoter is associated with preeclampsia.
abstract: Preeclampsia (PE) is a severe pregnancy-induced disorder characterized by hypertension and proteinuria and a leading cause of perinatal maternal-fetal mortality and morbidity in developing countries. Dysregulated human leukocyte antigen (HLA)-G was found in placentas as well as in maternal sera from PE patients; however, the reason for this difference is unknown. As accumulating evidence has confirmed that DNA methylation is an important mechanism for regulating gene expression, we sought to test the hypothesis that alteration in the DNA methylation of the HLA-G promoter region is responsible for decreased expression of HLA-G in PE. Bisulfite pyrosequencing showed that a series of CpG sites in the HLA-G promoter region were significantly more highly methylated in PE than in normal pregnancy (NP). Interestingly, the hypermethylated CpG sites were mostly reported to be binding sites of active transcription factors. To further investigate the regulation of HLA-G methylation, we also defined the expression patterns of DNA methyltransferases (DNMTs) in placental tissue using immunohistochemistry and quantitative polymerase chain reaction analyses. Here, we demonstrate that DNMT-1 is overexpressed and HLA-G expression is reduced in PE women when compared with NP. Furthermore, both treatment with the DNMT inhibitor 5-aza-2'-deoxycytidine and specific knockdown of DNMT-1 using siRNAs can significantly increase the expression level of HLA-G in a trophoblastic cell line, indicating the potential mechanism of DNMT-1-mediated DNA methylation in HLA-G regulation. Taken together, our research confirms that DNMT-1-mediated promoter hypermethylation of HLA-G is associated with PE. These findings provide new insights into the diagnosis and treatment of PE.
authors.affiliation: The Department of Obstetrics, Obstetrics and Gynecology Hospital, Fudan University, 419 FangXie Road, Shanghai 200011, PR China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Tang
authors.affiliation: The Department of Obstetrics, Obstetrics and Gynecology Hospital, Fudan University, 419 FangXie Road, Shanghai 200011, PR China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Department of Obstetrics, Obstetrics and Gynecology Hospital, Fudan University, 419 FangXie Road, Shanghai 200011, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.affiliation: The Department of Obstetrics, Obstetrics and Gynecology Hospital, Fudan University, 419 FangXie Road, Shanghai 200011, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Peng
authors.affiliation: The Department of Obstetrics, Obstetrics and Gynecology Hospital, Fudan University, 419 FangXie Road, Shanghai 200011, PR China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, PR China guweirong163@163.com.
authors.forename: Weirong
authors.initials: W
authors.lastname: Gu
authors.affiliation: The Department of Obstetrics, Obstetrics and Gynecology Hospital, Fudan University, 419 FangXie Road, Shanghai 200011, PR China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, PR China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Li
mesh_terms: D000328:Adult; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016022:Case-Control Studies; D002460:Cell Line; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059951:HLA-G Antigens / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D010920:Placenta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D014162:Transfection; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D059951:HLA-G Antigens; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine
keywords: DNA methylation; DNMT-1; HLA-G; preeclampsia