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.

ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

“…27 Critically, we also showed that viral overexpression of ΔFOSB in dorsal hippocampal neurons prevents learning, 27 and other groups have gone on to demonstrate that ΔFOSB is highly induced in dorsal hippocampus in human AD patients and mouse models of AD and that inhibition of this ΔFOSB can reverse cognitive deficits in AD mice. 28,29,88 The ventral hippocampus, though also important for learning and cognition, is more often correlated with emotional learning and associations between specific experiences and feelings of reward, fear, pain, or pleasure. ΔFOSB is induced in the ventral hippocampus by stress, antidepressants, and drugs of abuse, 31,40,58,61,77 and we and others have shown that ventral hippocampal ΔFOSB expression is critical for resilience to stress 31 and the antidepressant effects of ketamine.…”

Comparison of Fitness Cost and Virulence in Chromosome- and Plasmid-Mediated Colistin-Resistant Escherichia coli

“…CL-mcrR strains were subjected to plasmid stability assays as described previously (Bryksin and Matsumura, 2010). Ten microliter overnight seed cultures of the strains were inoculated in 10 mL LB medium without antibiotic (1:1000 ratio).…”

Circuit-specific hippocampal ΔFosB underlies resilience to stress-induced social avoidance

“…We found that Adra2a mRNA is downregulated in Neuro2a cells after ΔFosB overexpression (Fig. 5c), indicating that ΔFosB represses the Adra2a gene, as it represses other genes in dHPC 44,45 . In order to confirm this regulation, Neuro2a cells were transfected with Cas9 and FosB gRNA or the ΔFosB transcriptional repressor ΔJunD, and both conditions caused an increase in Adra2a mRNA (Fig.…”