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Review
. 2009 Feb 1;65(3):198-203.
doi: 10.1016/j.biopsych.2008.08.015. Epub 2008 Sep 24.

Epigenetic Regulation in Human Brain-Focus on Histone Lysine Methylation

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Free PMC article
Review

Epigenetic Regulation in Human Brain-Focus on Histone Lysine Methylation

Schahram Akbarian et al. Biol Psychiatry. .
Free PMC article

Abstract

Alterations in RNA levels are frequently reported in brain of subjects diagnosed with autism, schizophrenia, depression, and other psychiatric diseases, but it remains unclear whether the underlying molecular pathology involves changes in gene expression, as opposed to alterations in messenger RNA processing. Pre-clinical studies have revealed that stress, drugs, and a variety of other environmental factors lead to changes in RNA levels in brain via epigenetic mechanisms, including modification of histone proteins. A number of site-specific modifications of the nucleosome core histones-including the trimethylated forms of histone H3 lysines K4, K9, and K27-are of particular interest for postmortem research, because these marks differentiate between active and inactive chromatin and seem to remain relatively stable during tissue autolysis. Therefore, histone methylation profiling at promoter regions could provide important clues about mechanisms of gene expression in human brain during development and in disease. Intriguingly, mutations within the genes encoding the H3K9-specific methyltransferase, EHMT1, and the H3K4-specific histone demethylase, JARID1C/SMCX, have been linked to mental retardation and autism, respectively. In addition, the H3K4-specific methyltransferase, MLL1, is essential for hippocampal synaptic plasticity and might be involved in cortical dysfunction of some cases of schizophrenia. Together, these findings emphasize the potential significance of histone lysine methylation for orderly brain development and also as a molecular toolbox to study chromatin function in postmortem tissue.

Figures

Figure 1
Figure 1. Chromatin immunoprecipitation (ChIP) in postmortem brain
Schematic overview of ChIP in postmortem brain, starting with tissue homogenization, collection and purification of nuclei, followed by the optional step of immunotagging and fluorescence-activated sorting of nuclei (into neuronal and non-neuronal, for example), followed by nuclei lysis and enzymatic digestion of chromatin fibers and polynucleosomes) into mono-nucleosomes, followed by immunoprecipitation with site- and modification-specific anti-histone antibodies (anti-tri-methyl-H3-lysine 4, for example), followed by separation of DNA and histones, and quantification of specific DNA sequences in the immunoprecipitate, relative to input. See (38, 55, 58) for details.
Figure 2
Figure 2. Epigenetic determinants of dysregulated GABAergic gene expression in schizophrenia
A subset of GABAergic gene promoters, including GAD1 encoding GAD67, show a progressive upregulation in mRNA levels and open chromatin-associated histone H3-lysine (K) 4 trimethylation (blue tags) during the course of prefrontal development and maturation. Chromatin remodeling at the GAD1 locus is likely to involve MLL1 methyltransferase. A subset of subjects diagnosed with schizophrenia shows a deficit both in GAD1 mRNA levels and trimethylated H3K4. Treatment with the atypical antipsychotic, clozapine, leads to increased MLL1 recruitment, and H3K4 methylation at the GAD1 locus. Of note, these drug-induced methylation changes may not necessarily be accompanied by increased GAD1 mRNA. See (28) for details.

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