Genome-wide profiling reveals functional diversification of ?FosB gene targets in the hippocampus of an Alzheimer's disease mouse model.

ABSTRACT: The activity-induced transcription factor ?FosB has been implicated in Alzheimer's disease (AD) as a critical regulator of hippocampal function and cognition downstream of seizures and network hyperexcitability. With its long half-life (> 1 week), ?FosB is well-poised to modulate hippocampal gene expression over extended periods of time, enabling effects to persist even during seizure-free periods. However, the transcriptional mechanisms by which ?FosB regulates hippocampal function are poorly understood due to lack of identified hippocampal gene targets. To identify putative ?FosB gene targets, we employed high-throughput sequencing of genomic DNA bound to ?FosB after chromatin immunoprecipitation (ChIP-sequencing). We compared ChIP-sequencing results from hippocampi of transgenic mice expressing mutant human amyloid precursor protein (APP) and nontransgenic (NTG) wild-type littermates. Surprisingly, only 52 ?FosB gene targets were shared between NTG and APP mice; the vast majority of targets were unique to one genotype or the other. We also found a functional shift in the repertoire of ?FosB gene targets between NTG and APP mice. A large number of targets in NTG mice are involved in neurodevelopment and/or cell morphogenesis, whereas in APP mice there is an enrichment of targets involved in regulation of membrane potential and neuronal excitability. RNA-sequencing and quantitative PCR experiments confirmed that expression of putative ?FosB gene targets were altered in the hippocampus of APP mice. This study provides key insights into functional domains regulated by ?FosB in the hippocampus, emphasizing remarkably different programs of gene regulation under physiological and pathological conditions.

SUBMITTER: You JC 

PROVIDER: S-EPMC5800686 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature