LncRNA BACE1-AS: a link between heart failure and Alzheimer's disease

Abstract

Background: BACE1-antisense RNA (BACE1-AS) is a lncRNA antisense to the Beta-Secretase-1 (BACE1) gene encoding a key enzyme in the production of the β-amyloid peptide, associated to Alzheimer's disease (AD). In a previous study1, we showed that the BACE1-AS/BACE1 axis is activated in heart failure (HF) patients, leading to β-amyloid accumulation in failing hearts. Accordingly, BACE1-AS expression in different cultured cardiac cell types induced the expression of BACE1 and β-amyloid that, in turn, triggered apoptosis. The mechanisms underlying BACE1-AS action are not yet fully elucidated. Indeed, current models based on miRNA sponging or masking inducing BACE1 post-transcriptional stabilization may not recapitulate all BACE1-AS functions. Purpose: Our aim is to investigate the molecular mechanisms regulated by BACE1-AS in heart failure disease. Methods: BACE1-AS-pull-down, followed by RNA-Seq, was used to identify RNAs interacting with BACE1-AS in AC16 cardiomyocytes. Moreover, accessible chromatin sites induced by BACE1-AS overexpression were assayed by ATAC-Seq. Results: BACE1-AS pull-down identified 698 BACE1-AS interacting RNAs. Among these enriched transcripts, 69 were mapping to genomic enhancer regions that have been found to be hypo-methylated in AD brains2. After qPCR validation of the interactions identified by RNA-seq, the modulation of SEMA4D, ABCG1, GFRA2 and RIMBP2, which were under the control of a subset of these enhancers, was assayed upon BACE1-AS overexpression in cardiomyocytes. It was found that their expression was induced, supporting the functional interaction between BACE1-AS and the identified enhancer loci. To gain further insight into BACE1-AS function in cardiomyocytes, accessible chromatin sites induced by BACE1-AS overexpression were assayed by ATAC-Seq. Interestingly, 17 regions identified by this approach overlapped with enhancers that are hypo-methylated in AD brains. One of the accessible chromatin sites was the locus encompassing RNF214/BACE1/BACE1-AS that maps to active enhancer marks, indicating that BACE1-AS may regulate the expression of BACE1 transcriptionally. Conclusion: Collectively, these data suggest BACE1-AS as a node of shared disease-mechanisms between heart failure and AD.