MAPPING THE TRANSCRIPTIONAL REGULATORY NETWORK OF THE AMYLOID PRECURSOR PROTEIN INTRACELLULAR DOMAIN (AICD)

Abstract

AICD, the C-terminal tail generated from the proteolytic cleavage of the Amyloid Precursor Protein (APP), has been generating interest for its transcriptional modulatory roles. AICD has been hypothesized to have such a function as it is generated by a gamma-secretase-mediated regulated intramembrane proteolysis step, analogous to the generation of Notch intracellular domain (NICD), a well-known transcriptional regulator, from Notch. The AICD/Fe65/Tip60 ternary complex has been proposed as the working transcriptional regulatory complex and some of its target genes have been reported. However, our knowledge of the functions of AICD is still limited due to difficulties in detecting and manipulating the rapidly degraded peptide. Looking at AICD transcription modulation targets from a genome-wide perspective will aid our understanding of the role of AICD tremendously. To this end, AICD chromatin binding sites were investigated from a genome-wide perspective by performing Chromatin Immunoprecipitation coupled to deep DNA sequencing (ChIP-Seq) in SH-SY5Y cells stably over-expressing APP/AICD. Computational analysis revealed multiple highly significant DNA motifs that were enriched at the AICD binding sites, indicating that AICD may work with different partner transcription factors to regulate different subsets of target genes. Additionally, gene expression profiling of SH-SY5Y cells revealed genes that were differentially expressed with varying APP/AICD levels. The expression profile was used to complement the AICD chromatin binding profile to identify genes that are both bound and regulated by AICD. Since AICD has been found to be elevated in patients suffering from Alzheimer¿s Disease (AD) and may play a role in AD pathology, this study contributes to further insight into the potential role that AICD transcriptional modulation may have with respect to AD development.