A Polymorphic Microsatellite Repeat within the ECE-1c Promoter Is Involved in Transcriptional Start Site Determination, Human Evolution, and Alzheimer's Disease

Abstract

Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid ␤ content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG] m -[CA] n ECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.

An arterial-specific enhancer of the human endothelin converting enzyme 1 (ECE1) gene is synergistically activated by Sox17, FoxC2, and Etv2

“…Ece-1 function in the heart has been proposed to be important in the formation of the cardiac conduction system (Hall et al, 2004; Takebayashi-Suzuki et al, 2000). Four Ece-1 isoforms have been described (Schweizer et al, 1997; Valdenaire et al, 1999); the different ECE1 transcripts are initiated from distinct transcriptional start sites, which results in slight variations in the N-termini of the different proteins produced (Funke-Kaiser et al, 2000; Li et al, 2012; Orzechowski et al, 1997; Valdenaire et al, 1999). However, how ECE1 is controlled transcriptionally remains incompletely understood.…”

“…However, how ECE1 is controlled transcriptionally remains incompletely understood. Some analyses of proximal promoter elements in cell culture-based studies have been described (Funke-Kaiser et al, 2000; Li et al, 2012; Orzechowski et al, 1998; Orzechowski et al, 1997; Valdenaire et al, 1999), but the regulation of the ECE1 gene in vivo has not been addressed previously.…”

A potential association between the number of CA repeats in the promoter region of the ADAMTS9 gene with lymphatic metastasis of breast cancer

“…Recently, Li et al demonstrated that CA repeats within the endothelin-converting enzyme-1 (ECE-1c) gene promoter are highly polymorphic and harbor transcriptional start sites and CA repeat length, indicating shifted allelic frequency distributions. These data indicate that genomic repeat composition constitutes a novel core promoter element and affects transcriptional start site determination (29).…”

Structural and functional significance of microsatellites

“…A CpG-CA repeat within the human endothelin-converting enzyme-1 (ECE-1) promoter is highly polymorphic, harbours transcriptional start sites, it is able to recruit the transcription factors, poly(ADP)ribose polymerase-1 and splicing factors, it is functional regarding haplotype-specific promoter activity. Overall CpG-CA repeat composition of Alzheimer disease patients and controls is distinct [72]. A length polymorphism of GT repeats in the promoter region of the human heme oxygenase-1 (HO-1) gene modulates its gene transcription [73].…”