Screening reveals conserved and nonconserved transcriptional regulatory elements including an E3/E4 allele-dependent APOE coding region enhancer

被引：14

作者：

Chen, Hsuan Pu ^{[2
]}

Lin, Andy ^{[3
]}

Bloom, Joshua S. ^{[1
]}

Khan, Arshad H. ^{[1
]}

Park, Christopher C. ^{[1
]}

Smith, Desmond J. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Biomed Engn, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA

来源：

GENOMICS | 2008年 / 92卷 / 05期

关键词：

APOE; Bioinformatics; Enhancer; Luciferase; Nucleic acid regulatory sequences; Shotgun cloning; Silencer; SNPs; Transcription;

D O I：

10.1016/j.ygeno.2008.07.009

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

We performed an unbiased experimental search for enhancers and silencers in a 153-kb region containing the human apolipoprotein (APO) E/C1/C4/C2 gene cluster using shotgun cloning into a luciferase vector. A continuum of transcriptional effect sizes was observed, possibly explaining the limited success of bioinformatics in identifying regulatory regions. We identified nine statistically significant enhancers and five silencers functional in either liver or astrocyte cells, including two previously known enhancers. Only two of the fourteen elements contained conserved noncoding sequences. Within the coding sequence of the APOE gene we identified an enhancer for the E4 allele associated with Alzheimer's disease, but not E3. The single nucleotide polymorphism (SNP) causing the E4/E3 amino acid substitution was responsible for these variations, potentially explaining the higher expression levels of E4. Our results suggest a wider variety of mammalian transcriptional regulatory sequences than is currently recognized and that these may include coding region SNPs. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：292 / 300

页数：9

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