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Amyloid protein-mediated differential DNA methylation status regulates gene expression in Alzheimer's disease model cell line

Title
Amyloid protein-mediated differential DNA methylation status regulates gene expression in Alzheimer's disease model cell line
Authors
Sung H.Y.Choi E.N.Ahn Jo S.Oh S.Ahn J.-H.
Ewha Authors
오세관안정혁성혜윤
SCOPUS Author ID
오세관scopus; 안정혁scopus; 성혜윤scopus
Issue Date
2011
Journal Title
Biochemical and Biophysical Research Communications
ISSN
0006-291XJCR Link
Citation
vol. 414, no. 4, pp. 700 - 705
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. © 2011 Elsevier Inc.
DOI
10.1016/j.bbrc.2011.09.136
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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