title: MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor α gene.
abstract: BACKGROUND
  Estrogen receptor α (ERα) has been shown to protect against atherosclerosis. Methylation of the ERα gene can reduce ERα expression leading to a higher risk for cardiovascular disease. Recently, microRNAs have been found to regulate DNA methyltransferases (DNMTs) and thus control methylation status in several genes. We first searched for microRNAs involved in DNMT-associated DNA methylation in the ERα gene. We also tested whether statin and a traditional Chinese medicine (San-Huang-Xie-Xin-Tang, SHXXT) could exert a therapeutic effect on microRNA, DNMT and ERα methylation.
  
  
  RESULTS
  The ERα expression was decreased and ERα methylation was increased in LPS-treated human aortic smooth muscle cells (HASMCs) and the aorta from rats under a high-fat diet. MicroRNA-152 was found to be down regulated in the LPS-treated HASMCs. We validated that microRNA-152 can knock down DNMT1 in HASMCs leading to hypermethylation of the ERα gene. Statin had no effect on microRNA-152, DNMT1 or ERα expression. On the contrary, SHXXT could restore microRNA-152, decrease DNMT1 and increase ERα expression in both cellular and animal studies.
  
  
  CONCLUSIONS
  The present study showed that microRNA-152 decreases under the pro-atherosclerotic conditions. The reduced microRNA-152 can lose an inhibitory effect on DNA methyltransferase, which leads to hypermethylation of the ERα gene and a decrease of ERα level. Although statin can not reverse these cascade proatherosclerotic changes, the SHXXT shows a promising effect to inhibit this unwanted signaling pathway.
authors.affiliation: Department of Medical Genetics, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yung-Song
authors.initials: YS
authors.lastname: Wang
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Chou
authors.forename: Ku-Chung
authors.initials: KC
authors.lastname: Chen
authors.forename: Hsin-Yun
authors.initials: HY
authors.lastname: Cheng
authors.forename: Ruey-Tay
authors.initials: RT
authors.lastname: Lin
authors.forename: Suh-Hang Hank
authors.initials: SH
authors.lastname: Juo
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047628:Estrogen Receptor alpha; D008070:Lipopolysaccharides; C550856:MIRN152 microRNA, human; D035683:MicroRNAs; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619382:Dnmt1 protein, rat