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Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions
Seizure incidence is increased in Alzheimer’s disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of ΔFosB, a transcription...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268090/ https://www.ncbi.nlm.nih.gov/pubmed/32536852 http://dx.doi.org/10.3389/fnins.2020.00472 |
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author | Stephens, Gabriel S. Fu, Chia-Hsuan St. Romain, Corey P. Zheng, Yi Botterill, Justin J. Scharfman, Helen E. Liu, Yin Chin, Jeannie |
author_facet | Stephens, Gabriel S. Fu, Chia-Hsuan St. Romain, Corey P. Zheng, Yi Botterill, Justin J. Scharfman, Helen E. Liu, Yin Chin, Jeannie |
author_sort | Stephens, Gabriel S. |
collection | PubMed |
description | Seizure incidence is increased in Alzheimer’s disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of ΔFosB, a transcription factor with a long half-life. Even the infrequent seizures that spontaneously occur in transgenic mice expressing human amyloid precursor protein (APP) lead to persistent increases in ΔFosB in the hippocampus, similar to what we observed in patients with AD or temporal lobe epilepsy. ΔFosB epigenetically regulates expression of target genes, however, whether ΔFosB targets the same genes when induced by seizures in different neurological conditions is not clear. We performed ChIP-sequencing to assess the repertoire of ΔFosB target genes in APP mice and in pilocarpine-treated wildtype mice (Pilo mice), a pharmacological model of epilepsy. These mouse models allowed us to compare AD, in which seizures occur in the context of high levels of amyloid beta, and epilepsy, in which recurrent seizures occur without AD-specific pathophysiology. Network profiling of genes bound by ΔFosB in APP mice, Pilo mice, and respective control mice revealed that functional domains modulated by ΔFosB in the hippocampus are expanded and diversified in APP and Pilo mice (vs. respective controls). Domains of interest in both disease contexts involved neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and neuroinflammation. To assess the gene targets bound by ΔFosB regardless of seizure etiology, we focused on 442 genes with significant ΔFosB binding in both APP and Pilo mice (vs. respective controls). Functional analyses identified pathways that regulate membrane potential, glutamatergic signaling, calcium homeostasis, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and qPCR measurements in independent mice detected altered expression of several ΔFosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced ΔFosB can bind genes in patterns that depend on seizure etiology, but can bind other genes regardless of seizure etiology. Understanding the factors that underlie these differences, such as chromatin accessibility and/or abundance of co-factors, could reveal novel insights into the control of gene expression in disorders with recurrent seizures. |
format | Online Article Text |
id | pubmed-7268090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-72680902020-06-12 Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions Stephens, Gabriel S. Fu, Chia-Hsuan St. Romain, Corey P. Zheng, Yi Botterill, Justin J. Scharfman, Helen E. Liu, Yin Chin, Jeannie Front Neurosci Neuroscience Seizure incidence is increased in Alzheimer’s disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of ΔFosB, a transcription factor with a long half-life. Even the infrequent seizures that spontaneously occur in transgenic mice expressing human amyloid precursor protein (APP) lead to persistent increases in ΔFosB in the hippocampus, similar to what we observed in patients with AD or temporal lobe epilepsy. ΔFosB epigenetically regulates expression of target genes, however, whether ΔFosB targets the same genes when induced by seizures in different neurological conditions is not clear. We performed ChIP-sequencing to assess the repertoire of ΔFosB target genes in APP mice and in pilocarpine-treated wildtype mice (Pilo mice), a pharmacological model of epilepsy. These mouse models allowed us to compare AD, in which seizures occur in the context of high levels of amyloid beta, and epilepsy, in which recurrent seizures occur without AD-specific pathophysiology. Network profiling of genes bound by ΔFosB in APP mice, Pilo mice, and respective control mice revealed that functional domains modulated by ΔFosB in the hippocampus are expanded and diversified in APP and Pilo mice (vs. respective controls). Domains of interest in both disease contexts involved neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and neuroinflammation. To assess the gene targets bound by ΔFosB regardless of seizure etiology, we focused on 442 genes with significant ΔFosB binding in both APP and Pilo mice (vs. respective controls). Functional analyses identified pathways that regulate membrane potential, glutamatergic signaling, calcium homeostasis, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and qPCR measurements in independent mice detected altered expression of several ΔFosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced ΔFosB can bind genes in patterns that depend on seizure etiology, but can bind other genes regardless of seizure etiology. Understanding the factors that underlie these differences, such as chromatin accessibility and/or abundance of co-factors, could reveal novel insights into the control of gene expression in disorders with recurrent seizures. Frontiers Media S.A. 2020-05-28 /pmc/articles/PMC7268090/ /pubmed/32536852 http://dx.doi.org/10.3389/fnins.2020.00472 Text en Copyright © 2020 Stephens, Fu, St. Romain, Zheng, Botterill, Scharfman, Liu and Chin. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Stephens, Gabriel S. Fu, Chia-Hsuan St. Romain, Corey P. Zheng, Yi Botterill, Justin J. Scharfman, Helen E. Liu, Yin Chin, Jeannie Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions |
title | Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions |
title_full | Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions |
title_fullStr | Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions |
title_full_unstemmed | Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions |
title_short | Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions |
title_sort | genes bound by δfosb in different conditions with recurrent seizures regulate similar neuronal functions |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268090/ https://www.ncbi.nlm.nih.gov/pubmed/32536852 http://dx.doi.org/10.3389/fnins.2020.00472 |
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