Elsevier

Biological Psychiatry

Volume 65, Issue 3, 1 February 2009, Pages 198-203
Biological Psychiatry

Review
Epigenetic Regulation in Human Brain—Focus on Histone Lysine Methylation

https://doi.org/10.1016/j.biopsych.2008.08.015Get rights and content

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.

Section snippets

Histone Modifications

The nucleosome as the elementary unit of chromatin comprises 146 base pair (bp) of DNA wrapped around an octamer of four different histone proteins (H2A, H2B, H3, and H4) (17). Both the nucleosome core histones and some of their variants (H3.1, H3.3, etc) are subject to covalent modifications of specific residues located primarily at the amino-terminal tail; these include lysine acetylation, methylation, SUMOylation, and ubiquitinylation; arginine methylation; serine phosphorylation; and

Methodological Considerations and Limitations

Histones are bound with very high affinity to genomic DNA (51), and so it is not surprising that bulk levels of nucleosome-bound DNA remain relatively unchanged, even in brain tissues subject to 30 hours of autolysis (38). However, in a living cell, the chromatin architecture of the interphase nucleus is complex. In addition to an array of subnuclear bodies (e.g., nucleosomes, PML bodies, Cajal bodies), highly organized three-dimensional chromatin domains and transcription factories exist that

Gene Expression in Development and Disease Is Associated with Histone Methylation Changes at Gene Promoters Human Brain

Both the metabotropic (GRM1-7) and ionotropic (e.g., N-methyl d-aspartate, amino-3-hydroxy-5-methylisoxazole propionate, and kainate) glutamate receptor genes undergo dynamic, region- and cell-specific changes in expression during the course of brain development. In human brain, these developmental and region-specific changes of mRNA levels are accompanied by complementary alterations in H3K4 di- and tri-methylation at the sites of the corresponding promoters (31). Likewise, the progressive

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