A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests
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{"title"=>"A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests", "type"=>"journal", "authors"=>[{"first_name"=>"Frederick A.", "last_name"=>"Schroeder", "scopus_author_id"=>"7102761018"}, {"first_name"=>"Michael C.", "last_name"=>"Lewis", "scopus_author_id"=>"7404188597"}, {"first_name"=>"Daniel M.", "last_name"=>"Fass", "scopus_author_id"=>"7006157343"}, {"first_name"=>"Florence F.", "last_name"=>"Wagner", "scopus_author_id"=>"35184404400"}, {"first_name"=>"Yan Ling", "last_name"=>"Zhang", "scopus_author_id"=>"56470838500"}, {"first_name"=>"Krista M.", "last_name"=>"Hennig", "scopus_author_id"=>"36664641800"}, {"first_name"=>"Jennifer", "last_name"=>"Gale", "scopus_author_id"=>"55614556700"}, {"first_name"=>"Wen Ning", "last_name"=>"Zhao", "scopus_author_id"=>"7403942414"}, {"first_name"=>"Surya", "last_name"=>"Reis", "scopus_author_id"=>"7102060134"}, {"first_name"=>"Douglas D.", "last_name"=>"Barker", "scopus_author_id"=>"7401896009"}, {"first_name"=>"Erin", "last_name"=>"Berry-Scott", "scopus_author_id"=>"37007498700"}, {"first_name"=>"Sung Won", "last_name"=>"Kim", "scopus_author_id"=>"46661129500"}, {"first_name"=>"Elizabeth L.", "last_name"=>"Clore", "scopus_author_id"=>"56630964700"}, {"first_name"=>"Jacob M.", "last_name"=>"Hooker", "scopus_author_id"=>"16417545700"}, {"first_name"=>"Edward B.", "last_name"=>"Holson", "scopus_author_id"=>"6602230262"}, {"first_name"=>"Stephen J.", "last_name"=>"Haggarty", "scopus_author_id"=>"6601955305"}, {"first_name"=>"Tracey L.", "last_name"=>"Petryshen", "scopus_author_id"=>"6603208126"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84881507348", "sgr"=>"84881507348", "pui"=>"369566744", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"23967191", "doi"=>"10.1371/journal.pone.0071323"}, "id"=>"6697e93a-65d3-3faf-bc13-b76dd97d5f7f", "abstract"=>"Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary--albeit often ineffective--treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.", "link"=>"http://www.mendeley.com/research/selective-hdac-12-inhibitor-modulates-chromatin-gene-expression-brain-alters-mouse-behavior-two-mood", "reader_count"=>80, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>4, "Researcher"=>16, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>25, "Student > Postgraduate"=>6, "Other"=>4, "Student > Master"=>8, "Student > Bachelor"=>7, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>4, "Researcher"=>16, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>25, "Student > Postgraduate"=>6, "Other"=>4, "Student > Master"=>8, "Student > Bachelor"=>7, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>7, "Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>13, "Agricultural and Biological Sciences"=>30, "Neuroscience"=>7, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Chemistry"=>11, "Psychology"=>3, "Social Sciences"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>13}, "Neuroscience"=>{"Neuroscience"=>7}, "Chemistry"=>{"Chemistry"=>11}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>30}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>7}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}}, "reader_count_by_country"=>{"United States"=>1, "Ireland"=>1, "United Kingdom"=>3}, "group_count"=>6}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1169618"], "description"=>"<p>(<b>a</b>) Schematic of experimental design with 10-day administration of Cpd-60 (45 mg/kg, i.p.). (<b>b</b>) Chromatin was immunoprecipitated with an anti-histone H4K12ac-antibody followed by qPCR targeting regions 1.0 or 0.2 kB upstream or 0.5 kB downstream from the transcription start site (TSS). Transcripts upregulated by Cpd-60 treatment had increased histone acetylation at promoter regions upstream, but not downstream, of the TSS in Cpd-60 treated tissue compared to vehicle. *p<0.05, **p<0.01, t-test of Cpd-60 versus vehicle.</p>", "links"=>[], "tags"=>["Biochemistry", "drug discovery", "Computational biology", "genomics", "Genome expression analysis", "Molecular genetics", "gene expression", "genetics", "epigenetics", "Histone modification", "chromatin", "Model organisms", "Animal models", "mouse", "neuroscience", "neurophysiology", "Motor systems", "Behavioral neuroscience", "Mental health", "psychiatry", "Mood disorders", "schizophrenia", "immunoprecipitation", "nucleus", "accumbens", "cpd-60", "treated"], "article_id"=>772410, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Frederick A. Schroeder", "Michael C. Lewis", "Daniel M. Fass", "Florence F. Wagner", "Yan-Ling Zhang", "Krista M. Hennig", "Jennifer Gale", "Wen-Ning Zhao", "Surya Reis", "Douglas D. Barker", "Erin Berry-Scott", "Sung Won Kim", "Elizabeth L. Clore", "Jacob M. Hooker", "Edward B. Holson", "Stephen J. Haggarty", "Tracey L. Petryshen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071323.g005", "stats"=>{"downloads"=>4, "page_views"=>49, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chromatin_immunoprecipitation_ChIP_of_nucleus_accumbens_from_Cpd_60_treated_mice_/772410", "title"=>"Chromatin immunoprecipitation (ChIP) of nucleus accumbens from Cpd-60 treated mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:37:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169613"], "description"=>"<p>Chronic SAHA (25 mg/kg, i.p.) or Cpd-60 (45 mg/kg, i.p.) significantly increased acetylation of histone H2B(tetra-acetylated), H3K9 and H4K12 in cortex, ventral striatum and hippocampus one hour after the 10<sup>th</sup> daily treatment (arbitrary units, relative to vehicle control). Representative western blots are shown with total levels of histone H3 (H3pan) and histone H4 (H4pan) used as loading controls. *p<0.05, t-test of Cpd-60 or SAHA versus vehicle. <i>n = </i>6 mice/group.</p>", "links"=>[], "tags"=>["Biochemistry", "drug discovery", "Computational biology", "genomics", "Genome expression analysis", "Molecular genetics", "gene expression", "genetics", "epigenetics", "Histone modification", "chromatin", "Model organisms", "Animal models", "mouse", "neuroscience", "neurophysiology", "Motor systems", "Behavioral neuroscience", "Mental health", "psychiatry", "Mood disorders", "schizophrenia", "hdac", "inhibitors", "histone", "acetylation"], "article_id"=>772405, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Frederick A. Schroeder", "Michael C. Lewis", "Daniel M. Fass", "Florence F. Wagner", "Yan-Ling Zhang", "Krista M. Hennig", "Jennifer Gale", "Wen-Ning Zhao", "Surya Reis", "Douglas D. Barker", "Erin Berry-Scott", "Sung Won Kim", "Elizabeth L. Clore", "Jacob M. Hooker", "Edward B. Holson", "Stephen J. Haggarty", "Tracey L. Petryshen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071323.g002", "stats"=>{"downloads"=>4, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_HDAC_inhibitors_on_histone_acetylation_in_mouse_brain_/772405", "title"=>"Effects of HDAC inhibitors on histone acetylation in mouse brain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:37:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169620", "https://ndownloader.figshare.com/files/1169625", "https://ndownloader.figshare.com/files/1169627", "https://ndownloader.figshare.com/files/1169629"], "description"=>"<div><p>Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary – albeit often ineffective – treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with <i>in vivo</i> engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.</p></div>", "links"=>[], "tags"=>["Biochemistry", "drug discovery", "Computational biology", "genomics", "Genome expression analysis", "Molecular genetics", "gene expression", "genetics", "epigenetics", "Histone modification", "chromatin", "Model organisms", "Animal models", "mouse", "neuroscience", "neurophysiology", "Motor systems", "Behavioral neuroscience", "Mental health", "psychiatry", "Mood disorders", "schizophrenia", "selective", "hdac", "inhibitor", "modulates", "alters", "mood-related"], "article_id"=>772412, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Frederick A. Schroeder", "Michael C. Lewis", "Daniel M. Fass", "Florence F. Wagner", "Yan-Ling Zhang", "Krista M. Hennig", "Jennifer Gale", "Wen-Ning Zhao", "Surya Reis", "Douglas D. Barker", "Erin Berry-Scott", "Sung Won Kim", "Elizabeth L. Clore", "Jacob M. Hooker", "Edward B. Holson", "Stephen J. Haggarty", "Tracey L. Petryshen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0071323.s001", "https://dx.doi.org/10.1371/journal.pone.0071323.s002", "https://dx.doi.org/10.1371/journal.pone.0071323.s003", "https://dx.doi.org/10.1371/journal.pone.0071323.s004"], "stats"=>{"downloads"=>11, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_Selective_HDAC_1_2_Inhibitor_Modulates_Chromatin_and_Gene_Expression_in_Brain_and_Alters_Mouse_Behavior_in_Two_Mood_Related_Tests_/772412", "title"=>"A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-08-14 02:37:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169616"], "description"=>"<p>(<b>a</b>) Heatmaps illustrating transcript expression changes in mouse brain following chronic HDAC inhibitor treatment for 10 days. Cpd-60 (45 mg/kg, i.p.) significantly upregulated (red) or downregulated (blue) a similar number of transcripts in prefrontal cortex (PFC), nucleus accumbens (NAc), and hippocampus (HIP). Expression changes following SAHA treatment (25 mg/kg, i.p.) were predominantly localized to HIP. (<b>b</b>) Venn diagrams illustrate that only 1–10 genes were similarly regulated by Cpd-60 and SAHA treatment depending on brain region. Genes included in heatmaps and Venn diagrams have ≥1.2-fold expression change compared to vehicle (ANOVA p<0.05 with Tukey’s HSD <i>post hoc</i> test). (<b>c</b>) qPCR validation of a subset of genes with significantly altered expression following Cpd-60 treatment as determined by microarray analysis. *p<0.05, t-test of Cpd-60 or SAHA compared to vehicle.</p>", "links"=>[], "tags"=>["Biochemistry", "drug discovery", "Computational biology", "genomics", "Genome expression analysis", "Molecular genetics", "gene expression", "genetics", "epigenetics", "Histone modification", "chromatin", "Model organisms", "Animal models", "mouse", "neuroscience", "neurophysiology", "Motor systems", "Behavioral neuroscience", "Mental health", "psychiatry", "Mood disorders", "schizophrenia", "hdac", "inhibitor"], "article_id"=>772408, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Frederick A. Schroeder", "Michael C. Lewis", "Daniel M. Fass", "Florence F. Wagner", "Yan-Ling Zhang", "Krista M. Hennig", "Jennifer Gale", "Wen-Ning Zhao", "Surya Reis", "Douglas D. Barker", "Erin Berry-Scott", "Sung Won Kim", "Elizabeth L. Clore", "Jacob M. Hooker", "Edward B. Holson", "Stephen J. Haggarty", "Tracey L. Petryshen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071323.g004", "stats"=>{"downloads"=>0, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_expression_changes_in_mouse_brain_following_chronic_HDAC_inhibitor_treatment_/772408", "title"=>"Gene expression changes in mouse brain following chronic HDAC inhibitor treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:37:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169614"], "description"=>"<p>(<b>a</b>) Timecourse of locomotor activity in response to and (<b>b</b>) total locomotor activity summed over 80 min following acute amphetamine challenge (3.5 mg/kg, i.p.; Time ‘0’ indicated by arrow). Hyperlocomotion in response to amphetamine was significantly reduced in mice chronically treated with Cpd-60 (45 mg/kg, i.p.) but not with SAHA (25 mg/kg, i.p.). (<b>c</b>) Time spent immobile in the forced swim test was significantly decreased in mice treated chronically with Cpd-60 but not SAHA compared to vehicle treated control mice. *p<0.05, **p<0.01, ANOVA with Least Significant Difference <i>post hoc</i> test.</p>", "links"=>[], "tags"=>["Biochemistry", "drug discovery", "Computational biology", "genomics", "Genome expression analysis", "Molecular genetics", "gene expression", "genetics", "epigenetics", "Histone modification", "chromatin", "Model organisms", "Animal models", "mouse", "neuroscience", "neurophysiology", "Motor systems", "Behavioral neuroscience", "Mental health", "psychiatry", "Mood disorders", "schizophrenia", "cpd-60", "mood-related", "behaviors"], "article_id"=>772406, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Frederick A. Schroeder", "Michael C. Lewis", "Daniel M. Fass", "Florence F. Wagner", "Yan-Ling Zhang", "Krista M. Hennig", "Jennifer Gale", "Wen-Ning Zhao", "Surya Reis", "Douglas D. Barker", "Erin Berry-Scott", "Sung Won Kim", "Elizabeth L. Clore", "Jacob M. Hooker", "Edward B. Holson", "Stephen J. Haggarty", "Tracey L. Petryshen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071323.g003", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_Cpd_60_treatment_on_mood_related_behaviors_in_mice_/772406", "title"=>"Effect of Cpd-60 treatment on mood-related behaviors in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:37:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169611"], "description"=>"<p>(<b>a</b>) Chemical structure of SAHA and Cpd-60. (<b>b</b>) <i>In vitro</i> IC<sub>50</sub> (µM) for HDAC 1-9 by SAHA and Cpd-60 using recombinant human HDAC enzymes and HDAC class-specific substrates. Inhibitor and substrate were incubated for 60 min (HDAC4-9) or 180 min (HDAC1-3)<sup>a</sup> to control for HDAC1-3 inhibition by slow-binding test compounds. (<b>c</b>) <i>In vitro</i> binding affinity (K<sub>i</sub>) and kinetics (half-life ‘T<sub>1/2′</sub> in minutes) for HDAC 1, 2 and 3 incubated with SAHA or Cpd-60 (10 µM). (<b>d</b>) H4K12 acetylation levels in HEK293 cells following 24 hr ‘constant’ exposure to DMSO, SAHA (20 µM) or Cpd-60 (20 µM) and 6 hr after drug ‘washout’ (media change) with tubulin loading control. (<b>e</b>) Dose response plots for induction of histone H4K12 acetylation in cultured primary mouse neuronal cells by SAHA or Cpd-60 for 24 hr. Cells with histone acetylation signals above an intensity threshold of >99.5% (“bright green cells”) are plotted as a percentage normalized to DMSO control. EC<sub>50</sub> values for H4K12 acetylation were 0.60 µM and 72 µM for SAHA and Cpd-60, respectively. (<b>f</b>) <i>In vivo</i> mouse brain pharmacokinetics following acute systemic administration of SAHA (25 mg/kg, i.p.) or Cpd-60 (45 mg/kg, i.p.).</p>", "links"=>[], "tags"=>["Biochemistry", "drug discovery", "Computational biology", "genomics", "Genome expression analysis", "Molecular genetics", "gene expression", "genetics", "epigenetics", "Histone modification", "chromatin", "Model organisms", "Animal models", "mouse", "neuroscience", "neurophysiology", "Motor systems", "Behavioral neuroscience", "Mental health", "psychiatry", "Mood disorders", "schizophrenia", "characterization", "classes", "hdac"], "article_id"=>772403, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Frederick A. Schroeder", "Michael C. Lewis", "Daniel M. Fass", "Florence F. Wagner", "Yan-Ling Zhang", "Krista M. Hennig", "Jennifer Gale", "Wen-Ning Zhao", "Surya Reis", "Douglas D. Barker", "Erin Berry-Scott", "Sung Won Kim", "Elizabeth L. Clore", "Jacob M. Hooker", "Edward B. Holson", "Stephen J. Haggarty", "Tracey L. Petryshen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071323.g001", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vitro_and_in_vivo_characterization_of_two_structural_classes_of_HDAC_inhibitors_/772403", "title"=>"<i>In vitro</i> and <i>in vivo</i> characterization of two structural classes of HDAC inhibitors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:37:52"}

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Relative Metric

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