Byun, Catherine Jeonghae and Seo, Jungwon and Jo, Sangmee Ahn and Park, Yoon Jung and Klug, Maja and Rehli, Michael and Park, Moon-Ho and Jo, Inho (2012) DNA methylation of the 5 '-untranslated region at+298 and+351 represses BACE1 expression in mouse BV-2 microglial cells. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 417 (1). pp. 387-392. ISSN 0006-291X,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | AMYLOID PRECURSOR PROTEIN; PLASMA HOMOCYSTEINE; ALZHEIMERS-DISEASE; BETA-SECRETASE; S-ADENOSYLHOMOCYSTEINE; STEM-CELLS; INCREASES; GENE; HYPOMETHYLATION; PRESENILIN-1; Alzheimer's disease; 5 '-Untranslated region; BACE1; DNA methylation; Microglial cells |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 May 2020 13:17 |
| Last Modified: | 20 May 2020 13:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19376 |
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