title: Amyloid protein-mediated differential DNA methylation status regulates gene expression in Alzheimer's disease model cell line.
abstract: The Swedish mutation of amyloid precursor protein (APP-sw) has been reported to dramatically increase beta amyloid production through aberrant cleavage at the beta secretase site, causing early-onset Alzheimer's disease (AD). DNA methylation has been reported to be associated with AD pathogenesis, but the underlying molecular mechanism of APP-sw-mediated epigenetic alterations in AD pathogenesis remains largely unknown. We analyzed genome-wide interplay between promoter CpG DNA methylation and gene expression in an APP-sw-expressing AD model cell line. To identify genes whose expression was regulated by DNA methylation status, we performed integrated analysis of CpG methylation and mRNA expression profiles, and identified three target genes of the APP-sw mutant; hypomethylated CTIF (CBP80/CBP20-dependent translation initiation factor) and NXT2 (nuclear exporting factor 2), and hypermethylated DDR2 (discoidin domain receptor 2). Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored mRNA expression of these three genes, implying methylation-dependent transcriptional regulation. The profound alteration in the methylation status was detected at the -435, -295, and -271 CpG sites of CTIF, and at the -505 to -341 region in the promoter of DDR2. In the promoter region of NXT2, only one CpG site located at -432 was differentially unmethylated in APP-sw cells. Thus, we demonstrated the effect of the APP-sw mutation on alteration of DNA methylation and subsequent gene expression. This epigenetic regulatory mechanism may contribute to the pathogenesis of AD.
authors: Department of Biochemistry, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-ku, Seoul 158-710, Republic of Korea.
authors: Hye Youn
authors: HY
authors: Sung
authors: Eun Nam
authors: EN
authors: Choi
authors: Sangmee
authors: S
authors: Ahn Jo
authors: Seikwan
authors: S
authors: Oh
authors: Jung-Hyuck
authors: JH
authors: Ahn
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D000070818:Discoidin Domain Receptors; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D039502:Nuclear Cap-Binding Protein Complex / Q000235:genetics; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011975:Receptors, Mitogen / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D039502:Nuclear Cap-Binding Protein Complex; D011975:Receptors, Mitogen; D000077209:Decitabine; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D001374:Azacitidine