DNA methylation of the 5 '-untranslated region at+298 and+351 represses BACE1 expression in mouse BV-2 microglial cells
- Authors
- Byun, Catherine Jeonghae; Seo, Jungwon; Jo, Sangmee Ahn; Park, Yoon Jung; Klug, Maja; Rehli, Michael; Park, Moon-Ho; Jo, Inho
- Issue Date
- 6-1월-2012
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Keywords
- Alzheimer' s disease; 5 ' -Untranslated region; BACE1; DNA methylation; Microglial cells
- Citation
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.417, no.1, pp.387 - 392
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
- Volume
- 417
- Number
- 1
- Start Page
- 387
- End Page
- 392
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/109092
- DOI
- 10.1016/j.bbrc.2011.11.123
- ISSN
- 0006-291X
- Abstract
- BACE1, which cleaves the amyloid precursor protein, is the rate-limiting enzyme for beta-amyloid peptide production, leading to the pathogenesis of Alzheimer's disease (AD). A high plasma level of homocysteine, acting as a potent methyltransferase inhibitor, is assumed to be a risk factor for AD onset. Using the demethylating drug 5-aza-2'-deoxycytidine (5-Aza), we tested whether and how BACE1 expression is regulated in mouse BV-2 microglial cells. 5-Aza increased both BACE1 mRNA and protein levels in a dose-dependent manner. Bisulfite-sequencing analysis revealed that two CpG sites at positions +298 and +351 in the 5'-untranslated region (5'-UTR) of the BACE1 gene were specifically demethylated in BV-2 cells treated with 5-Aza. In silico analysis showed that the +351 site is the STAT3/CTCF-binding site; the function of the +298 site has not been identified. To assess whether these two CpG sites play an important role in 5-Aza-induced transcriptional activation of BACE1, we constructed a BACE1 gene promoter including the 5'-UTR (-1136 to +500) fused to a CpG-free luciferase gene (pCpGL-BACE1) and its mutant pCpGL-BACE1-AA, which has substituted CG dinucleotides at the two CpG sites of pCpGL-BACE1 to AA. Promoter analysis showed a significant decrease (similar to 30%) in the activity of pCpGL-BACE1-AA compared with that of pCpGL-BACE1. Furthermore, in vitro methylation of these two reporter constructs showed a complete silencing of their promoter activities. Our data demonstrate that BACE1 gene expression is regulated by DNA methylation of at least two CpG sites at positions +298 and +351 in the 5'-UTR in BV-2 microglial cells. (C) 2011 Elsevier Inc. All rights reserved.
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