Abstract
BACE1 gene encodes for β-Site amyloid β precursor protein (APP)-cleaving enzyme1, which is required for generating amyloid β protein(Aβ). Deposition of Aβ in brain plays an essential role in Alzheimer's Disease (AD) pathogenesis. BACE1 gene has a tissue-specific expression pattern and its expression is tightly regulated at transcriptional level. Core promoter is a minimal DNA sequence to direct transcription initiation and serves as a converging platform for the vast network of regulatory events. Here we identified the core promoter of human BACE1 gene, which is a 71 nucleotides region absent of typical known core promoter elements and is sufficient to initiate a basal transcription. Two novel DNA motifs, designated TCE1 and TCE2, were found to be involved in activating the transcription of human BACE1 gene in a synergistic way. Two single nucleotide mutations in these motifs completely abolished the promoter activity. In conclusion, our studies have demonstrated that novel DNA motif TCE1 and TCE2 in human BACE1 gene promoter are two essential cis-acting elements for BACE1 gene transcription. Studies on how these two motifs being regulated by different stimuli could provide insights into the molecular mechanisms underlying AD pathogenesis and pharmaceutical potentials of targeting these motifs for AD treatment.
Highlights
BACE1 gene encodes for b-Site amyloid b precursor protein (APP)-cleaving enzyme[1], which is required for generating amyloid b protein(Ab)
Our studies have demonstrated that novel DNA motif Transcription Critical Element 1 (TCE1) and Transcription Critical Element 2 (TCE2) identified in human BACE1 gene promoter are essential for controlling transcription of BACE1 gene
This observation indicates that the 600 bp region immediate upstream of ATG plays an important role in regulating BACE1 expression, consistent with our results that deleting the upstream region of -583 has no effects on promoter activity
Summary
BACE1 gene encodes for b-Site amyloid b precursor protein (APP)-cleaving enzyme[1], which is required for generating amyloid b protein(Ab). We identified the core promoter of human BACE1 gene, which is a 71 nucleotides region absent of typical known core promoter elements and is sufficient to initiate a basal transcription. Our studies have demonstrated that novel DNA motif TCE1 and TCE2 in human BACE1 gene promoter are two essential cis-acting elements for BACE1 gene transcription Studies on how these two motifs being regulated by different stimuli could provide insights into the molecular mechanisms underlying AD pathogenesis and pharmaceutical potentials of targeting these motifs for AD treatment. Transcription factor specificity protein 1 (Sp1) was the first one discovered to play an important role in regulating human BACE1 expression[19]. The majority of cis-acting elements of BACE1 gene promoter are located far from transcriptional start site (TSS). In-depth analysis of structure and function of BACE1 gene core promoter will greatly advance our understanding the transcriptional mechanisms of TATA-less core promoter and may benefit for developing new strategies in inhibiting BACE1 expression in prevention and treatment of Alzheimer’s disease
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