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

PLOS ONE, Nov 2019

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.

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

February Genome-wide profiling reveals functional diversification of ΔFosB gene targets in the hippocampus of an Alzheimer's disease mouse model Jason C. You 0 1 2 Gabriel S. Stephens 0 2 Chia-Hsuan Fu 0 2 Xiaohong Zhang 0 1 2 Yin Liu 0 2 Jeannie Chin 0 2 0 Institute of Neurological Disorders and Stroke NS085171 to JC; National Institute on Aging AG048710 to JCY; Margaret Q. Landenberger Biomedical Research Foundation research grant to JC; Hassel Family Foundation research grant to JC; National Institute of Neurological Disorders and Stroke NS086965 to JC. The funders had no role in 1 Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America, 2 Memory & Brain Research Center, Department of Neuroscience, Baylor College of Medicine , Houston , Texas, United States of America, 3 Department of Neurobiology and Anatomy, University of Texas Medical School at Houston , Houston, Texas , United States of America 2 Editor: Giuseppe Biagini, University of Modena and Reggio Emilia , ITALY The activity-induced transcription factor ΔFosB 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), ΔFosB 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 ΔFosB regulates hippocampal function are poorly understood due to lack of identified hippocampal gene targets. To identify putative ΔFosB gene targets, we employed high-throughput sequencing of genomic DNA bound to ΔFosB 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 ΔFosB 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 ΔFosB 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 ΔFosB gene targets were altered in the hippocampus of APP mice. This study provides key insights into functional domains regulated by ΔFosB in the hippocampus, emphasizing remarkably different programs of gene regulation under physiological and pathological conditions. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction The leucine zipper transcription factor ΔFosB belongs to the immediate early gene (IEG) family of proteins that are induced by neuronal activation to enact various activity-dependent programs in the cell [ 1 ]. ΔFosB is the truncated splice variant of FosB; this truncation is significant as it removes two C-terminal degron domains, making ΔFosB particularly resistant to proteasomal degradation [ 2 ]. Therefore, the half-life of ΔFosB is unusually long (~8 days in vivo), allowing it to modulate neuronal gene expression over prolonged periods of time [ 3 ]. The chronic and persistent nature of ΔFosB's effect on neuronal and network function has been well-characterized in the nucleus accumbens, where it modifies addictive behavior following repetitive exposure to drugs of abuse [ 4 ]. Such studies also showed that ΔFosB epigenetically enhances or silences transcription of various target genes via recruitment of histone-modifying enzymes such as p300/CBP or HDAC1 to target gene promoters, respectively [5±7]. ΔFosB expression is also increased in the hippocampus after seizure activity in various models of epilepsy where it has been used as a marker of activity [8±14]. Recently, we discovered that seizures and epileptiform activity also robustly increased ΔFosB expression in the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) expressing mutant human amyloid precursor protein (APP, line J20) as well as in pharmacological models of epilepsy [ 15, 16 ]. We found similar increases in ΔFosB expression in the hippocampus of AD patients and in patients with temporal lobe epilepsy [16]. The increase in ΔFosB expression had a significant impact on hippocampal function in APP mice, by suppressing expression of two genes essential for neuronal plasticity, Fos and Calb1, and by impairing hippocampus-dependent spatial memory [ 15, 16 ]. Treatment of APP mice with the antiepileptic drug levetiracetam reduced both (...truncated)


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Jason C. You, Gabriel S. Stephens, Chia-Hsuan Fu, Xiaohong Zhang, Yin Liu, Jeannie Chin. Genome-wide profiling reveals functional diversification of ∆FosB gene targets in the hippocampus of an Alzheimer's disease mouse model, PLOS ONE, 2018, Volume 13, Issue 2, DOI: 10.1371/journal.pone.0192508