Epigenetic Regulation in Human Brain—Focus on Histone Lysine Methylation

Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusettsm USA.
Biological psychiatry (Impact Factor: 9.47). 10/2008; 65(3):198-203. DOI: 10.1016/j.biopsych.2008.08.015
Source: PubMed

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.

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Available from: Schahram Akbarian, Aug 25, 2015
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    • "Methylated lysine residues of histone tails can be mono-, di-, or trimethylated (Lachner and Jenuwein 2002; Martin and Zhang 2005) and, depending on the lysine residue methylated, a differential effect on gene transcription is observed. For example, dimethylation of histone H3 lysine 9 (H3K9me2) promotes gene silencing (Rea et al. 2000; Covington et al. 2011), whereas trimethylation of histone H3 at lysine 4 (H3K4me3) promotes gene transcription (Schneider et al. 2004; Akbarian and Huang 2009). Furthermore, these different histone methylation modifications are regulated by a unique set of histone lysine methyltransferases (H/KMT) and histone lysine demethylases (H/KDM), suggesting a coordinated regulation of histone lysine methylation modifications controls gene transcription in neurons. "
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    • "Despite the epigenetic neuroscience field ' s youth, the hypothesis that methyltransferases/demethylases play an especially important role in cognition is gaining credi bility. Researchers are rapidly finding neurologic indications associated with dysregulated histone lysine methylation profiles, suggesting that more in-depth knowledge on the topic could bestow therapeutic value (Akbarian and Huang, 2009). As behavioral neuroscientists , we are consistently developing novel pharmaceutical approaches for cognitive enhancement, accelerated re-learning, and improved memory retention with cognitive disorders. "
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    • "AMERICAN JOURNAL OF MEDICAL GENETICS PART B of chromatin to transcriptional machinery [Berger, 2007; Akbarian and Huang, 2009]. We evaluated the 9p24.2 "
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    ABSTRACT: Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+) /dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. © 2013 Wiley Periodicals, Inc.
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