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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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Ac-H3K9K14 levels as a function of age in control subjects and those withschizophrenia. ChIP-qPCR assays were performed on postmortem BA46 fromcontrol subjects (closed circles, solid line) and those with schizophrenia(open circles, dashed line) representing a wide age range (group 2;n=32 subjects in total). Pearson's (r)values are shown in Table 2.
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fig3: Ac-H3K9K14 levels as a function of age in control subjects and those withschizophrenia. ChIP-qPCR assays were performed on postmortem BA46 fromcontrol subjects (closed circles, solid line) and those with schizophrenia(open circles, dashed line) representing a wide age range (group 2;n=32 subjects in total). Pearson's (r)values are shown in Table 2.

Mentions: To further explore the age effect on histone acetylation, we measuredac-H3K9K14 levels at the promoter regions of three of the neuronal genes,GAD1, TOMM70A and HTR2C, plus twooligodendrocyte-expressing genes, myelin basic protein (MBP) andUDP glycosyltransferase 8 (UGT8), and a ubiquitously-expressedgene, H1 histone family, member N (H1FNT) in the postmortemprefrontal cortex from a second cohort of subjects (group 2; Supplementary Table 1). This cohort was comprisedof young subjects (18–36 years of age) and old subjects(55–92 years of age) with schizophrenia and age-matchedcontrols (n=32 in total). Consistent with the results fromsubjects in group 1 above, Pearson's correlation analysis of ac-H3K9K14levels against age revealed strong negative correlation with age in normalsubjects (Table 2; Figure3), but not in subjects with schizophrenia, despite measuringlevels in a cohort of subjects with a greater age range (18–91 years).Examining our previous microarray data generated from the prefrontal cortexfrom case and control subjects ranging in age from 18–81 years(GEO accession #GSE21138),30,37 which consisted of one-halfof the same young subjects as used in this study, we similarly find that theexpression levels of these genes decreases with age (Supplementary 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)

Ac-H3K9K14 levels as a function of age in control subjects and those withschizophrenia. ChIP-qPCR assays were performed on postmortem BA46 fromcontrol subjects (closed circles, solid line) and those with schizophrenia(open circles, dashed line) representing a wide age range (group 2;n=32 subjects in total). Pearson's (r)values are shown in Table 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Ac-H3K9K14 levels as a function of age in control subjects and those withschizophrenia. ChIP-qPCR assays were performed on postmortem BA46 fromcontrol subjects (closed circles, solid line) and those with schizophrenia(open circles, dashed line) representing a wide age range (group 2;n=32 subjects in total). Pearson's (r)values are shown in Table 2.
Mentions: To further explore the age effect on histone acetylation, we measuredac-H3K9K14 levels at the promoter regions of three of the neuronal genes,GAD1, TOMM70A and HTR2C, plus twooligodendrocyte-expressing genes, myelin basic protein (MBP) andUDP glycosyltransferase 8 (UGT8), and a ubiquitously-expressedgene, H1 histone family, member N (H1FNT) in the postmortemprefrontal cortex from a second cohort of subjects (group 2; Supplementary Table 1). This cohort was comprisedof young subjects (18–36 years of age) and old subjects(55–92 years of age) with schizophrenia and age-matchedcontrols (n=32 in total). Consistent with the results fromsubjects in group 1 above, Pearson's correlation analysis of ac-H3K9K14levels against age revealed strong negative correlation with age in normalsubjects (Table 2; Figure3), but not in subjects with schizophrenia, despite measuringlevels in a cohort of subjects with a greater age range (18–91 years).Examining our previous microarray data generated from the prefrontal cortexfrom case and control subjects ranging in age from 18–81 years(GEO accession #GSE21138),30,37 which consisted of one-halfof the same young subjects as used in this study, we similarly find that theexpression levels of these genes decreases with age (Supplementary 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