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Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders.

Tang B, Dean B, Thomas EA - Transl Psychiatry (2011)

Bottom Line: Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities.We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E).Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities. Here, we have used chromatin immunoprecipitation-qPCR to measure levels of acetylated histone H3 at lysines 9/14 (ac-H3K9K14), two epigenetic marks associated with transcriptionally active chromatin, at the promoter regions of eight schizophrenia-related genes in n=82 postmortem prefrontal cortical samples from normal subjects and those with schizophrenia and bipolar disorder. We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E). Ac-H3K9K14 levels of several of the genes tested were significantly negatively associated with age in normal subjects and those with bipolar disorder, but not in subjects with schizophrenia, whereby low levels of histone acetylation were observed in early age and throughout aging. Consistent with this observation, significant hypoacetylation of H3K9K14 was detected in young subjects with schizophrenia when compared with age-matched controls. Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation. We further find that treatment with a histone deacetylase (HDAC) inhibitor alters the expression of several candidate genes for schizophrenia in mouse brain. These findings may have therapeutic implications for the clinical use of HDAC inhibitors in psychiatric disorders.

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Real-time PCR analysis for the indicated genes in subjects withschizophrenia, bipolar disorder and non-psychiatric controls. Real-time qPCRassays were performed as described in the materials and methods onpostmortem Brodmann area (BA) 10 from subjects with schizophrenia, bipolardisorder and matched controls (group 1; n=50 total). Datashown are gene expression values normalized by the housekeeping gene,B2M. Asterisks denote significant differences in expression asdetermined by one-way ANOVA followed by Student's t-test:*P<0.05; +P<0.08;**P<0.01;***P<0.001.
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fig1: Real-time PCR analysis for the indicated genes in subjects withschizophrenia, bipolar disorder and non-psychiatric controls. Real-time qPCRassays were performed as described in the materials and methods onpostmortem Brodmann area (BA) 10 from subjects with schizophrenia, bipolardisorder and matched controls (group 1; n=50 total). Datashown are gene expression values normalized by the housekeeping gene,B2M. Asterisks denote significant differences in expression asdetermined by one-way ANOVA followed by Student's t-test:*P<0.05; +P<0.08;**P<0.01;***P<0.001.

Mentions: We selected eight diverse “schizophrenia-related” genes (Table 1) for this study based on the followingcriteria: (1) genes showing differential expression in schizophreniaand/or bipolar disorder from published microarray studies;30, 31(2) genes showing CNS cell type-specific expression patterns based oncomparison with previous transcriptome studies performed on isolatedastrocytes, neurons and oligodendrocytes;32 (3) genes representing differentfunctions/pathways related to schizophrenia based on review of theliterature.20, 33, 34,35 Additionally, these selectedgenes are representative of different gene co-expression networks, based onour previous studies, which identified over 20 gene co-expression modules inthe prefrontal cortex from subjects with schizophrenia and bipolardisorder.36 We firsttested for expression differences for five neuronally expressed genes,GABAergic neurotransmission: GAD1; mitochondrialfunction/import: TOMM70A; neurotransmitter receptor signaling:serotonin 5-hydroxytryptamine receptor 2C (HTR2C) and regulator ofG protein signaling 4 (RGS4); signal transduction: proteinphosphatase, Mg2+/Mn2+ dependent, 1E(PPM1E) in the postmortem prefrontal cortex (Brodmann area 10)from a cohort of subjects with schizophrenia and bipolar disorder from theHarvard Tissue Resource Center (group 1; SupplementaryTable 1). Real-time qPCR analysis revealed decreasedexpression of HTR2C, TOMM70A, RGS4 and PPM1E in subjectswith schizophrenia and bipolar disorder compared with matched controls, anda decrease expression in GAD1 only in subjects with schizophrenia(Figure 1).


Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders.

Tang B, Dean B, Thomas EA - Transl Psychiatry (2011)

Real-time PCR analysis for the indicated genes in subjects withschizophrenia, bipolar disorder and non-psychiatric controls. Real-time qPCRassays were performed as described in the materials and methods onpostmortem Brodmann area (BA) 10 from subjects with schizophrenia, bipolardisorder and matched controls (group 1; n=50 total). Datashown are gene expression values normalized by the housekeeping gene,B2M. Asterisks denote significant differences in expression asdetermined by one-way ANOVA followed by Student's t-test:*P<0.05; +P<0.08;**P<0.01;***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3305989&req=5

fig1: Real-time PCR analysis for the indicated genes in subjects withschizophrenia, bipolar disorder and non-psychiatric controls. Real-time qPCRassays were performed as described in the materials and methods onpostmortem Brodmann area (BA) 10 from subjects with schizophrenia, bipolardisorder and matched controls (group 1; n=50 total). Datashown are gene expression values normalized by the housekeeping gene,B2M. Asterisks denote significant differences in expression asdetermined by one-way ANOVA followed by Student's t-test:*P<0.05; +P<0.08;**P<0.01;***P<0.001.
Mentions: We selected eight diverse “schizophrenia-related” genes (Table 1) for this study based on the followingcriteria: (1) genes showing differential expression in schizophreniaand/or bipolar disorder from published microarray studies;30, 31(2) genes showing CNS cell type-specific expression patterns based oncomparison with previous transcriptome studies performed on isolatedastrocytes, neurons and oligodendrocytes;32 (3) genes representing differentfunctions/pathways related to schizophrenia based on review of theliterature.20, 33, 34,35 Additionally, these selectedgenes are representative of different gene co-expression networks, based onour previous studies, which identified over 20 gene co-expression modules inthe prefrontal cortex from subjects with schizophrenia and bipolardisorder.36 We firsttested for expression differences for five neuronally expressed genes,GABAergic neurotransmission: GAD1; mitochondrialfunction/import: TOMM70A; neurotransmitter receptor signaling:serotonin 5-hydroxytryptamine receptor 2C (HTR2C) and regulator ofG protein signaling 4 (RGS4); signal transduction: proteinphosphatase, Mg2+/Mn2+ dependent, 1E(PPM1E) in the postmortem prefrontal cortex (Brodmann area 10)from a cohort of subjects with schizophrenia and bipolar disorder from theHarvard Tissue Resource Center (group 1; SupplementaryTable 1). Real-time qPCR analysis revealed decreasedexpression of HTR2C, TOMM70A, RGS4 and PPM1E in subjectswith schizophrenia and bipolar disorder compared with matched controls, anda decrease expression in GAD1 only in subjects with schizophrenia(Figure 1).

Bottom Line: Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities.We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E).Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities. Here, we have used chromatin immunoprecipitation-qPCR to measure levels of acetylated histone H3 at lysines 9/14 (ac-H3K9K14), two epigenetic marks associated with transcriptionally active chromatin, at the promoter regions of eight schizophrenia-related genes in n=82 postmortem prefrontal cortical samples from normal subjects and those with schizophrenia and bipolar disorder. We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E). Ac-H3K9K14 levels of several of the genes tested were significantly negatively associated with age in normal subjects and those with bipolar disorder, but not in subjects with schizophrenia, whereby low levels of histone acetylation were observed in early age and throughout aging. Consistent with this observation, significant hypoacetylation of H3K9K14 was detected in young subjects with schizophrenia when compared with age-matched controls. Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation. We further find that treatment with a histone deacetylase (HDAC) inhibitor alters the expression of several candidate genes for schizophrenia in mouse brain. These findings may have therapeutic implications for the clinical use of HDAC inhibitors in psychiatric disorders.

Show MeSH
Related in: MedlinePlus